Drug Therapy in the Geriatric Population – Module 4, Session 6

Our next speaker today is Dr. Darrell Abernathy. Darrell leads the development of pharmacological mechanism based safety program of the office of clinical pharmacology at the FDA. He brings more than 25 years of experience in medicine pharmacology including positions in academia practice and research Prior to joining the FDA. He served as chief scientific officer of the US be darrell received his MD and his PhD from the University of Kansas in 1976 he completed his residency in internal medicine at the University of Miami and his postdoctoral training in clinical pharmacology at Mass General Darryl’s research interest includes the effects on obesity on peripheral drug distribution the pharmacokinetics and pharmacodynamics Relationship of cardiovascular drugs in Ag. Please enjoy this lecture Well, good evening. I’m Darryl Abernathy. I currently work over at the Food and Drug Administration My background is an internist geriatric medicine and clinical pharmacology We spent much of a career in academics Focusing on on geriatric cardiovascular pharmacology so you see some of that tonight And then we’ll talk a little more generally about effects of medications in the older patient some might consider the the older patient and I’ll Defined that very loosely as yet another special population If if you talk in terms of drug development the special populations, of course are our patients with renal dysfunction patients with liver dysfunction Pediatric patients and and that’s about it But that is the older patient is not defined as a special population for those purposes and I happen to agree with that because really the the Definition of what is geriatric is quite. Unclear physiologic aging and chronolock chronological aging certainly don’t necessarily go in parallel and I usually say with a smile that Geriatric is really a few years older than you are so why don’t we go ahead and work through some Thinking about the interface of drugs and older people who have multiple illnesses Who have illnesses that have? Medications which are clearly shown to be effective for those illnesses. I Would say if if you want to interrupt as we go along and with questions that just fine So what we’ll try to do is to to point out these bullets When we talk when you hear this term polypharmacy used it’s oftentimes used in conjunction with older patients And the definition is fairly clearly five medications at one time There’s a newer term called hyper polypharmacy And that’s defined as more than ten to ten or more medications in an older person at one time As we’ll see this is not touching on uncommon sort of occurrence and quite honestly that’s totally understandable considering the multiple disease processes that older patients often have secondly, we will talk about the changes in cardiovascular function the interface with drug responses and show some Examples of how that plays itself out in terms of looking at clinical outcomes Thirdly, we’ll describe the changes in drug disposition in older people And provide some examples. I would say parenthetically that there are the literature on pharmacokinetics and aging is very large the literature in drug effects and aging is much much smaller and Then finally we’ll talk about a tool that we’ve developed over the past decade to try to understand What we believe are important effects on functional status in older patients with respect to medication exposure This is a simply one example of the multiple illnesses that patients in older age groups have There’s a burgeoning science of multi morbidity and trying to understand The role of multi multi morbidity in its interface with aging itself You can see here that in this particular study and this is just one of many There may be half of patients over the age of 65 have a diagnosis of arthritis Probably more than 40% Hypertension going down the list. And of course, there’s a lot of overlap. I think it’s probably Yeah, there’s a lot of overlap in these illnesses so that any one patient may well have three or four Medically important diagnoses all of which may benefit from drug therapy And so to get to the issue of how much exposure to medications do older patients have This is one study of many. This is taken from a panel of Los Angeles area nursing homes So these would be nursing home residence And you can see across a dozen nursing homes a mean of around 6 or so medications in each patient Now one can look at that and say gee that looks like a bad thing but it that needs to be put in the context that these are patients who have multiple diagnoses And many of these medication exposures may be really quite indicated and quite appropriate However, this has to be linked to what happens when multiple medications get put into a patient These are data from quite a while ago, but this has been replicated each decade up until the present and so I show this earlier data is simply to say this is not information it’s been replicated multiple times that the the incidence of adverse drug effect that’s a de Increases as a function of the number of medications and individuals concurrently taking and That we generally teach that the break in that line is five medications Concurrently or more and so that’s how the definition of polypharmacy came about and that that has been confirmed and really validated using ROC curves looking at the the characteristics of patient function and and the number of concurrent medications But as you can see when the medication number gets higher That it’s not a linear relationship of the likelihood of an adverse drug effect So let’s talk for a few minutes about one particular important drug Set of drug targets that would be the cardiovascular system. And so let’s look at a few examples of how age changes or it may impact on the pharmacodynamics of cardiovascular medications First what’s the the landscape? These are data taken from the Baltimore longitudinal study on Aging? This is a National Institute on Aging funded project that’s been going on for about 50 years now Simply looking at individuals following them through life and now following a number of their offspring through life and doing Repeated measurements every two years on these individuals they come into the center at the ni a and have a wide variety of behavioral functional and in this case cardiovascular measurements made since the Goal of this study is to look at quote normative aging And as these patients developed illnesses, they continue in this study but that that’s really part of normative aging the interface of Disease onset And age, so what are the cardiovascular features that relate to the older individual? First if we look at total intravascular volume and somewhat decreased peripheral vascular resistance is increased There’s a tendency to decrease cardiac output. Tendency is a very soft term The reason for making it soft is that at rest? Cardiac output and older patients even up to a fairly extreme of age is not so different than younger individuals however, exercise cardiac output or the ability to respond to Needing to have an increase in cardio put is impaired in older patients importantly barrel reflexes are Altered with decreased baroreceptor sensitivity in older patients and we’ll see the consequences of that in a few minutes There’s increased blood pressure variability so beat to beat variability and variability over the 24-hour period If we think in terms of the contracted intravascular volume That flies in the face of these patients tend to be what we would call low renin patients and so there – one can see a Physiologic change occurring that’s dissociating plasma renin activity in intravascular volume And then finally, we’ll look at some data that evaluates vascular endothelial function in older individuals This is a I believe the first demonstration that beta adrenergic receptor Activation is impaired as a function of age. This too has been replicated many many many times And interestingly even with many grants and many studies the full mechanism of this has not worked out But it’s there and it’s clearly so this particular study shows what’s called isoproterenol? Resistance so giving isoproterenol a predominantly beta one adrenergic agonist increases the heart rate So the question here is how much isoproterenol is required to increase the heart rate? 25 beats per minute as a function of increasing age and you can see that the dosage of either paternal goes up rather dramatically as a function of increasing age As I say the conclusion from this is that beta-1 adrenergic function Is impaired with increased age? And I won’t show the data but but workers at Stanford some years ago showed that beta-2 adrenergic Mediated bayes of peripheral vasodilation is also blunted as a function of increasing age Now what about beta adrenergic Function and what we have to think about alpha adrenergic function here as well these are studies that we did some years ago looking at the Responses to labetalol in in this these are a selected pair of younger and older women And then looking at the change in heart rate That would be the beta blocking effect of labetalol as a function of drug concentration You can see that in the younger individual at relatively low drug concentrations rather to matic decrease in heart rate what one would expect from an intravenous administration of a drug like this and in the older individual a Much much greater exposure of labetalol required to achieve the same reduction in heart rate Suggesting then that that the capacity to suppress beta adrenergic function is impaired As a function of increasing age as well Now if we look at blood pressure responses these are data from the same study This is looking at systolic blood pressure in younger and older individuals and we can see that This is after an administration of an oral dose of labetalol in the under individuals little change in Systolic blood pressure over time after that this is a single dose of oral labetalol This would be typical if you think about it of administering doses of an oral beta blocking drug Of any sort not much change in blood pressure but if we look in the older individual a rather dramatic decrease in systolic blood pressure over the first while after exposure and then slowly returning to to The baseline so what is this suggesting? Well, it’s saying that we had that there is blunted Capacity to respond to an alpha mediated vaso dilating response This is an alpha one blocker as well as a beta blocker and with that incapacity to do that and then the incapacity to have with the basic peripheral vasodilation a reflex tachycardia because of the impaired beta adrenergic Responsiveness. I really rather marked a decrease in blood pressure as compared to younger individuals Now let’s move to another target that That is important with regard to aging and and then look at some data that relate to age-related changes If we think about calcium flux from the extracellular to the intracellular space is demonstrated by this cartoon Calcium gets into the cell in a number of ways but two very important ones are through the the l-type calcium Channel and through the receptor operated calcium channel. You would say. Well, what is this the alpha 1 receptor? is a great example of this particular chant receptor that modulates the flux of calcium and so we’ve looked at some data that indicate that their changes in this Potent to this receptor operated calcium channel. Let’s look for a few minutes at dynamic responses to drugs which block the l-type calcium channel So first let’s think about what the structural changes are in older people As we begin now to think about drugs which act on on vascular function These are data again accumulated from a variety of sources Mostly autopsy, but but then some biopsy resources as well What are the arterial changes related to normal aging that would be not in patients not with hypertension or other? Marked atherosclerosis For there’s increased calcium and collagen. Of course, this is Accentuated in patients with atherosclerosis or long-standing hypertension There’s reduced arterial compliance in other words impaired large large vessel ability to dilate With with cardiac function increased pulse pressure. We mentioned that in other words a Greater difference between systolic and diastolic blood pressure We mentioned the barrel reflex sensitivity and we’ll talk a little bit more about that however, however If you want to put what barrel reflux function is and into a personal Context think about when you go from a supine posture to upright And why your blood pressure? Doesn’t drop dramatically And and your heart rate has a change that allows you to maintain that blood pressure an increase in heart rate in Older patients the capacity to have those reflux functions is impaired then in the small arteries and this is this is most likely the main reason for the increased peripheral vascular existence in older patients in a thickening of arterioles and as we mentioned increased peripheral vascular resistance So what are the consequences of these changes in thinking in a physiological model this is a a Idealized depiction but based on real data that Michael O’Rourke published in a textbook some years ago And it very nicely points up issues that relate to younger and older individuals So this is a pulse wave that some of you may be familiar with if one put a catheter into a into an artery particularly into a large artery one would see something like this with each heartbeat and What does this represent when the younger individual that’s what this is meant to represent with a quote normal blood pressure there’s a certain velocity of the pulse wave going down the or a Horta after a heartbeat and Then this will look familiar, but this would be the systolic part of the heartbeat and then with cardiac relaxation diastole occurring and then the ANSI Shara This lump here represents an important component in with cardiac function to permit coronary artery filling This is maintaining a pressure at the root of the aorta where the coronary arteries take off So we can see that this is occurring during diastole when the heart is relaxing allowing for an efficient coronary artery filling in the older individual with a stiff aorta And a order with decreased compliance a broader wider pulse pressure Resulting in a increased pulse wave velocity. So think of a any elastic tube as compared to a rigid tube And with the increased pulse wave velocity This insurer really represents the reflection of the pulse wave From the bifurcation the order back to That the the Reuter they order and we can see that this increased velocity results then In the end the NCC era occurring during systole so that when the heart is still in a contracted state is a critical time for a coronary artery if and So this send results, of course in a decreased reserve with regard to Do being able to maintain coronary filling? So based on that background of physiology let’s think about l-type calcium Channel blockers and their their effects in older individuals. This is a study again that we did some time ago looking and three age groups of normative people and So this is a pharmacokinetic curve. First of all, this is giving a dose of intravenous for a per mil the same dose in in three different groups of individuals and we can see in the younger individual a Elimination rate that would be consistent with many published studies and that is fairly rapid And an older individual some sense lower and in the older the older yet individual some somewhat slower Yeah in this particular study I would say that that the oldest individual in this age group was a hundred and one years old. It was a very charming elderly gentleman Now we see that Pharmacokinetic curve which could be replicated and we’ll talk about that in a little while across many different kinds of drugs for a per mil as a cy p38 remand This would be quite typical for what one would expect in terms of the disposition of the drug. What about its effects? first of all for a per mil in addition to be to causing peripheral vasodilation Also due to the l-type calcium Channels in atrial ventricular node of the heart and the sinoatrial node of the heart has effects there as well That is that it blocks atrial ventricular conduction And then decreases heart rate slightly not as much as a beta blocker But decreases heart rate slightly due to the SA node effects Now one might think and I have to say when we were doing this study We anticipated that the older individuals would be more sensitive to the even a little blocking effect of a drug like verapamil Simply because of the fibrosis of the conduction system it’s well documented with age and here were the findings that we had and that is that in the There we go in the younger individual we saw a concentration related prolongation of the electrocardiographic PR interval Which is a surface measurement that approximates AV nodal conduction And so we can see this delay and this would be why the drug is useful for the treatment of supraventricular tachycardias However, instead of an a heightened responsiveness even with an increased drug exposure if you remember from the pharmacokinetic curve The older individuals have less AV nodal conduction delay And so there’s a blunting of this capacity with regard to cardiac conduction as a function of age You might say then are these drugs less effective for the treatment of supraventricular Tachycardias for example as a function of increasing age and to my mom what to my knowledge the state that studies never been done Now what about effects of this This l-type calcium channel blocker and it’s peripheral vasodilator effects in this same patient population or the same subject population asserts that This is looking at the decrease in mean blood pressure after it a this would be the first dose of verapamil in Younger individuals some decrease in blood pressure and older perhaps a greater increase in the much older Perhaps the somewhat greater increase yet with a huge variability in all the groups So you’d say well does this say that the older individuals have greater peripheral vasodilation due to the l-type calcium Channel blocker fective the drug and I’d pause that no, that’s not the case here We can see the decrease in the pardon me the change in heart rate At the same time that these blood pressures are measured so that the younger individuals have a reflex tachycardia protecting their blood pressure the decrease in blood pressure the older individuals don’t have any change in heart rate and Thus without the increase in cardiac output a greater decrease in blood pressure and the much older Individuals actually have a decrease in heart rate. This is even after an acute intravenous dose of verapamil Well, we believe this this is showing it’s uncovering the sinoatrial node suppressing effects of verapamil in these individuals And we can see that with this Perhaps even decrease in heart rate, perhaps an even greater decrease increase in the drop in blood pressure So the heart rate responses with the l-type calcium channel it’s blocking exposures Decreased heart rate responses. We believe those are due to impaired reflex sympathetic outflow and function It’s possible and and that can’t be ruled out that there are parasympathetic changes with age as well those studies studies such as that done in dogs with a by a colleague of mine from the past who works at San Francisco now suggested and in fact, that was true that vagal withdrawal it does change with age as well, but we’ve not been able to confirm that in people and in a Hypothesis that there may be differing sensitivity to calcium channel blocker at the sinus node in older individuals Now let’s move off for a bit to the to the peripheral vasculature and particularly the vascular endothelium and its interface with vascular smooth muscle We can see here then Paul van who does view of what a vascular Endothelial cell looks like and how it interacts with a vascular smooth muscle cell. I Would say at the outset this is a highly simplified diagram that there are many more Local interactions between these two cells that are shown here, but we’re going to focus on the nitric oxide part of this interaction which appears to be a very importantly so that the the question is or the issue is When when vascular endothelium are stimulated by a variety of stimuli? They release nitric oxide diffusing to the vascular smooth muscle and then activating a cascade of events via cyclic GMP mechanisms to result in vascular smooth muscle Relaxation thus vasodilation and decrease in blood pressure So what happens is a function of increasing age I want you to focus on the dark blue bars So the study design here These are some data that we’ve generated again a while back and this is looking then at one of the the potent stimuli for Endothelial mediated production of nitric oxide and then resulting in vascular smooth muscle relaxation acetylcholine now what’s known and this was really the first observation to get at the role of endothelial Relaxing factors was it was very early called before was identified as nitric oxide. Was that if one? Administers a steel choline directly to vascular smooth muscle it contracts However, the observation and this was by Bob birch got the observation in early 1980s was that if one did that then? Two intact vasculature one saw relaxation and it didn’t make sense And so they worked and they worked and then a group of three people ultimately got the Nobel Prize for understanding the importance of endothelial mediated function and endothelial interactions with vascular smooth muscle so the state of design here is looking at younger and older individuals and their responsiveness to acid teal choline So what’s the dose to cause a 50% maximal response of? to a steel choline mediated vasodilation and younger as compared to older individuals and the point to be made here is a substantially higher dose of a steel choline is required to result in maximal vasodilation in the older individuals Now I would say that there are a number of other factors That that cause the same sort of change and we attempted in this study to control for All of them and we hope that we succeeded But certainly cigarette smoking would result in the same sort of finding Hyperlipidemia results in the same sort of finding and patients with long-standing hypertension have impaired at STO choline mediated endothelial responses Now if we move this to another Important vascular set of vasculature. That would be the coronary system. We see similar sorts of findings These are data that Were obtained in individuals who were referred for cardiac? Catheterization and at the time of the catheterization were found to have clean corners so first I would I would say that the qualification would be these may well not have been totally normal patients Or they wouldn’t have had some sort of atypical chest pain being referred for cardiac catherization But secondly, they did not have a thorough sclerotic disease. And so if we look at These individuals as a function of age what this is showing is the percentage increase in Coronary blood flow. This would be the maximal increase in coronary blood flow to a local Acetylcholine infusion into the coronary artery and we can see in younger individuals as much as a six-fold increase in coronary blood flow with this maximal vasodilating stimulus however, as the the with increasing age this response appears to be Decreasing rather markedly actually, and so this these data are consistent with what I showed you for the peripheral vasculature. I Didn’t mention what the study design was here, but these studies are taken from a peripheral arterial function This is infusion of a steel choline into the brachial artery and then measuring forearm blood flow distal to that a steel choline infusion Now let’s move from those form of what I would call pharmacodynamic changes of aging to drug disposition and older people As I said, there’s a much larger Database for drug disposition probably because drugs are easy to measure drug responses are much harder to measure First what happens to drugs? I suspect you’ve seen many variants of this slide in this course already But this is a very simple month the simple slide Point of view drug goes in it’s either cleared by the kidney or it’s chanting its bio transformed by the liver into Metabolites which may be active or inactive and then ultimately cleared by some process and that is shown here to be in the kidney But it might also be via the GI tract with biliary transport. It might be a Pulmonary with exhalation or so on but the real point is that the clearance mechanism results Ultimately in the detoxification or the removal of the drug from the system So when we think about drug metabolism and this would be the liver part of that that diagram It’s generally split into these two phase one drug bio transformations or degradation bio transformations and phase two drug bio transformations or synthetic or conjugative drug bio transformations We’ll be talking primarily about the phase one drug bio Transformations because these are the ones that change as a function of increasing age the phase two bio Transformations don’t change much. I suspect you’ve already heard that with liver disease. The same is true And so that that appears to be a consistent finding that these these mechanisms have drug Biotransformation are more resistant to disease So what are some of the phase one drugs that older people might get these are just examples there’s a huge long list of them For that you could go to This drug interaction table at this website. I Think that’s been changed just in the last month to the Flockhart website how this is because the individual who developed this Passed away last Thanksgiving in any case Looking at these examples. You see some fairly familiar drugs The the predominant drug of biotransformation is Cyp3a4 But I generally say that there are other ISO enzymes of the three a series that have importance in some cases so to keep it more general But then we’ll see other pathways that biotransformation as well So, let’s look at a prototype cy p 3a in younger versus older individuals This is from a study that we did a long time ago. Looking at tries a lamb or Halcyon a sedative hypnotic drug and then looking at a typical pharmacokinetic curve in a younger versus an older woman these were healthy individuals and of course these this pair was selected because they Represented extremes not the mead but simply to demonstrate that thinking about this being a log plot That in this case is a rather dramatic difference in exposure to tries to him after the same dose Now if we look at another sedative hypnotic and a Conscious sedation drug midazolam Tradename versed these again are data from a study that we did some years ago And this is a more typical see why p38? Individuals And here we can see if we look at young younger men and younger women They said this was defined as under the age of 40 older men and older women defined as as over the age of 65 That we can see that there’s some decrease in clearance of midazolam in the these two Separate age groups and the general teaching. Is that probably about a 30% decrease in cyp 388 a drug bio transformations if we look across many different drug substrates and many different studies Now what about drugs which undergo renal excretion These are drugs that are not metabolized or excreted unchanged and so here are some examples And some of these will look familiar and some of them will look quite dated And so I suspect many or most of you have seen this equation before but the question is how do you characterize renal function in As a function of age or really as a function of weight or what have you there are many different Equations have been developed in variations of many different equations This one is is one that’s widely used with regard to drug development and drug dosing and the the Cockroft Gault equation many of you may be more familiar with the mdrd equation Another equation that’s been developed that has some slight variation from this equation But it is frankly much more complicated to Determined both of these now are generally generated on lab reports or the mdrd reported equation result itself Generated on lab reports when the relevant data are submitted with the laboratory in any case What what I’d like to have you take a look here or what the elements of this relationship are So this would be an estimate of creatinine clearance. And so if we look at this an important factor is age a Factor is wait and then serum creatinine and here the the standard approach is to reduce the estimate of creatinine clearance by 15% and females as compared to males Why because serum cream circulating serum? creatinine is really a function of lean body mass and lean body mass is decreased and in female so we look across the population as compared to males So the the changes in renal clearance an in renal function occur with age as you can see If we if we put this into a graph an XY axis graph decreases across a Population as a function of increasing age and the clearance of these renal eclair drugs decreases in parallel with that Now it’s important to note that For example drugs which are not only filtered at the kidney but secreted actively like penicillins and others That it appears that the active secretory Processes of renal clearance go down pretty much in parallel to the the non active filtration sources so that these drugs also decrease pretty much in parallel with a decrease in Creatinine clearance or measured or estimated creatinine clearance as a function of age? So if we did a summary of what are the pharmacokinetic changes and older people Let’s quickly run through them and I’ve shown you data on some of these and not on others for a reason Been a lot of studies done looking at gastrointestinal absorption changes with aging because it’s well known that that that gastric acidity decreases with age And it’s quite clear looking across the decades and many studies that there’s not a whole lot of change in GI absorption drugs the central compartment volume of drugs in other words It’s rapidly distributing volume doesn’t look like it changes very much as a function of age The peripheral compartment and those that this would be then the volume of distribution That would be measured and that you would see when thinking in terms of the volume of the distribution of a drug that moves really In relationship to body composition and this is your respective of age. So that drugs which are a relatively water-soluble will have a decreased volume distribution simply because the the proportion of body fat and non non fat mass changes with age with with lean body fat lean body mass decreasing and fat mass increase in both males and females Here we’re not talking about only obese individuals really across the spectrum and then drugs which are highly fat soluble have increased distribution in in Individuals with increased relatively relative fat mass therefore in older individuals as a group Much has been written about Protein binding of drugs because the thought is that of course drugs The only drug that is not bound to plasma proteins is available for action other than administering single doses of drug For example the use of midazolam for onset of anesthesia Or so on this doesn’t really make much difference with regard to the disposition of drugs and although Albumen drug binding decreases with age an alpha 1 acid like o protein binding may change with age That’s frankly a little unclear. We published a paper saying that that it goes up in aging However, it’s unclear whether that’s really inflammation or or the aging process itself but with chronic drug dosing which is the usual circumstance, it’s really the the clearance of the drug is Dictated by the free concentration of the drug so that these changes of in drug binding and therefore changes in circulating total drug concentration Really are not relevant and it’s the clearance of the free drug itself that is relevant with regard to the drug Available. So those changes in drug clearance we talked about would relate to then the free drug Now what about the bio transformation reactions while we talked about cyp3a4 actions decreasing in this range across a wide range of substrates here are other important roots of phase one drug biotransformation This group have been studied rather extensively and some of them change some some of them not so much you’ll see that that a Couple are three in here actually are polymorphic to d6 to c9 and 2c 19. And I think it’s important to emphasize the the polymorphic or the genetic differences are Much much more important with regard to drug clearance than any age-related change in any of these Enzyme activity then as we mentioned phase 2 drug bio transformations are not much changed in age now Let’s talk for a few minutes about the whole individual and the kind of the real-world circumstance of that individual receiving either one or many medications and what the impact maybe So first this is simply looking at use of medications of prevalence of medication use Across different indications and this would be than a surrogate really for the incidence of diagnosis In individuals and so this is looking at decades of age 65 to 75 75 to 85 and over 85 And we can see that taking any hypertensive drugs 80% of patients Hyperlipidemia drugs 70 or 80% and on down the list and this is simply pointing out Then that older individuals will indeed be taking multiple medications These are more recent data And again, this can be replicated many times and probably everybody in geriatrics has got at least one publication so when we think about the effects of Polypharmacy or multiple medications and individual the real question is what’s important? well, what’s important really is the patient’s functional status and So, how can we? understand drug effects on the patient’s overall functional status because it’s quite clear that that Measures of functional status are a much better marker of longevity than specific physiologic measures Or other very individual measurements so as a nice example for patients with congestive heart failure if we think about the Determinants of mortality their walking speed is more important marker than their cardiac output Walking speed being then a very complex composite functional measurement Now what drugs what drugs and we? Believe may have importance with regard to changes in these functional measurements Well there there’s a fairly good understanding that anticholinergic drugs Are not the older person’s friend And an increasing understanding that said drugs have one sort or another are not the older person’s friends. That’s what we tried to do Was to develop a way of thinking about this that could be then taken into the population So that’s what we mean by here to develop an evidence base model to assess functional risk and benefit to medication exposure in older patients This is something called the drug burden index there are a few other of these measures I’ll describe this one in some detail partly because we developed it but then partly because we’ve we have validated across multiple populations and so the idea is first of all We believe based on literature and and clinical experience that drugs with anticholinergic effects are drugs that we should think about very carefully when I think Considering exposing older patients to them similarly drugs with sedative effects. And so then Rather than count medications, how can we put this in the context of drug exposure? And so what we did? Was to simply use this relationship if you think about it. This is a variant of kind of an e max concentration model or and the idea is What then is the dose that the patients receiving? What’s the minimum? recommended daily dose from the label of the drug with the idea being that this is probably not a Maximal effect it’s certainly probably not exactly an EC or a D or a dose-response 50% However, it’s somewhere in between zero and 100. And so putting Using this relationship and then using an additive relationship with drugs. This is Attempt to make some estimate of the drug exposure and its relationship to effect This is exposure based on drug dose not not drug concentration because this is the data really more commonly available And and Look across populations to understand whether information can be gleaned from this kind of a parameter So what are the functional measures that? That have been used in a date. I’ll show you first They were developed by several investigators, but really quite predominantly by the National Institute on Aging And if you look at these functional measurements, and then think about the bet they sort of make sense chair stance getting up and down from a chair and the speed with which you do it the time for a six meter walk and Then a time for a six meter walk with a narrow course and then standing balanced so these are these are complex functions that require the the use of many different sensory systems and so these have been turned then into a composite measure It’s called the Health Asian body composition score. Why because a longitudinal study again funded by ni a That looked at a large group of people in Memphis, Tennessee in Pittsburg, Pennsylvania and then related these functions over a period of years to morbidity and mortality in this population And these were the things that fell out changes in these functions were good predictors of morbidity and mortality This was validated then in another population These pay these individuals I would say are what we call high functioning These are people in the community who are seem to be getting along reasonably. Well At an earlier time. There was a very large multicenter study With this name? Its acronym is a PC of an unusual acronym but one that I guess you can remember but same idea Except these are lower functioning individuals patients who are perhaps teetering on being able to stay at home And so it looked like that this works across this particular composite score works across a variety of different levels of individual function What are the functional measures of sedation? Well that the digit symbol substitution test taken out of the Wechsler intelligence scale is a very common one And so it looks at a variety of things psychomotor performance concentration It’s what are the findings This is in looking at the individuals in this health aging and body composition study this is about a thousand individuals and looking then at Using that drug burden index And this then would be looking at drugs which have anticholinergic Effects these are not only drugs that are administered for their anticholinergic effects But you’ll remember that a variety of other drugs have anticholinergic effects as off-target effects, for example neuroleptics antidepressants and so forth so we looked at drugs which do have anticholinergic effects and then put them into the equation to develop an Anticholinergic burden and then looked at that in relationship to the health ABC score In these individuals in red and the digit simple substitution Test in blue and we can see there’s a fairly clear relationship with increasing anticholinergic burden and decreasing health ABC score in digit simple substitution test scoring If we look at sanity burden We again see these are drugs then that have sedating effects however, do not have anticholinergic effects if you think about it for a moment many drugs Which are anticholinergic are also sedating in this particular study. We called them Anticholinergic and then this is separating out the others. This would include things like benzodiazepines and other things which rather clearly don’t have Anticholinergic effects, but we see perhaps a less dramatic Association, but again the same general idea with increasing exposure to sedative drugs Impairments in these functions And so if you’d say well those lines look interesting but what do they mean well look the development of the particulars of functional tests this health ABC score was rather comprehensive because the interest of the investigators in this study actually continues or evaluations of the data to do The interest really had to do with with disease associations with a whole variety of psychosocial Associations with this score and then we simply added the drug as the drug exposures on top of all of that but with that other background What what? From the other studies have been done the changes we saw in in the health ABC score and the the Digit symbol substitutions test would be approximately equivalent to the patient having three additional physical Comorbidities things like hypertension diabetes, etc, etc Or the same as patients with some cognitive impairment depression or anxiety So we believe that that’s saying a 1-point increase in drug burn burden index Probably is a meaningful thing to the individual and we saw more than that With increasing exposure to anticholinergic and sedative drugs Now in addition to that we looked at this that same population That’s a longitudinal study and so we’re able to look at one three and five years To look first at changes in drug burden, which weren’t much And secondly what the cumulative? Exposure was in other words simply doing an area end of the curve of the drug burden X index exposure over five years to see how that Predicted then the functional outcomes at year six and the short answer is it did quite well So You’d say well that’s interesting That’s in one study in Memphis and Pittsburgh are not necessarily representative of the world and I couldn’t agree with you more So it turns out that a collaborator in this study who actually was doing a fellowship with me at the time Went back to Sydney Australia took a faculty position And then it applied essentially the same methodology to a aging men project in Sydney, Australia looking at community dwelling older men same finding Looking another cohort in Australia looking at low functioning individuals and same finding and then looking in What they’re what’s shown here is Department of Veterans Affairs? And arresting Lee they would say these are patients and repatriation hospitals. I like them but in any case Again that as these data have evolved these findings were similar as well Now in the United States, there’s an another study. This was headed up out of Johns Hopkins Looking it’s called the Women’s Health and Ageing study. And so these are Individuals women in the city of Baltimore Who’ve been characterized as in the lower 30% of physical function. So these are people who are barely hanging on being able to stay at home And so we did the same evaluation in that study and again came up with the same fund. So we believe that that With these what I guess I’d call cross-sectional Evaluations that that this is a robust finding And we also believe that this drug burden index is a useful tool to think in terms of drug exposure That’s being further evaluated now in longitudinal studies one starting in New Zealand just now And another one going on in Australia, and we’re starting to work with the health the World Health Organization to see about incorporating this kind of a evaluation because you know in the World Health Organization there are the first of all the essential medicines list, but then optimal dosing recommendations Across population so the countries with less well-developed regulatory Organization Of access to at least some information So we’re working to see if if indeed this might be useful to further inform the dosage recommendations for that that activity so Finally I’m sure that you’ve either read in the newspaper or you’ve read in journal articles that old people are not Included in clinical trials. We don’t know enough about how drugs work in old people Why does the FDA continue to allow drug studies to occur which are looking really only at healthy? Individuals and then the drugs get put out in the community All I can say to the last comment. Is that the guidelines? from both the United States and the European Union This would be the European Medicines Agency Are quite clear and that is that patients over the age of 75 with multiple illnesses should be included in studies Patients with illness is consistent with what would be in the community. Does that happen? Well, probably not as much as it should but there’s a continuing effort to try to to try to Improve the exposure and the the understanding of drug effects during the drug development process And this is simply a statement saying yes, the the patient should be included in clinical trials an important question of course is do drug do older patients have the same responses to take pick your class of medications, but say Antihypertensives or hypolipidemic sore other medications to which there’s a hikes And the short answer is yes, it looks like that if you do stratified analyses Post-hoc of data so that the responses are not so different and so that’s somewhat reassuring However coupled with that Uniformly the adverse of effect or the adverse event profile is increased as a function of increasing age Now this is saying should a Trial be powered to independently assess efficacy and what we’re calling multiple chronic condition or multiple multiple Multi morbidity patients and that’s an ongoing discussion Because of course that number one increases the cost of the trial there for the increase increases the cost of the drug development program And so on now with regard to safety profile At the moment that’s mostly done in older individuals After a drug has been approved and is on the market. Can we do better than that or learn more? at an earlier time point well, perhaps some So, what are the goals for for Therapeutics in the older patient. Well, I think these are obvious but To have efficacy to decrease morbidity and mortality as a function of the use of medications Trying to minimize drug-related problems and improve quality of life There’s a very active effort going on In a number of parts of the world really more in Europe and Australia than in the United States Called D prescribing initiatives. What’s quite clear? Is that when one goes into an older population that Is exposed to fairly extreme polypharmacy in a judicious way? Working with the the primary caregivers starts removing medications in general The patients will do better with fewer medications not more. And so I think if you’re saying well hor What are we going to hear going forward? There’s there’s going to be really increasing emphasis on not exposing Oh people to more medications But trying to very judiciously expose them to only the medications that have a clear benefit to that end There’s another effort in trying to modify treatment guidelines treatment guidelines as they currently exist early disease specific So there’s a treatment guideline for congestive heart failure for diabetes and on down the list a Clever researcher over at Johns Hopkins has been a lead, but there are a number of people working in this space Saying well, what if we took the typical eighty year old person who had four or five illnesses? And we said, okay. Let’s follow the treatment guidelines for each of the illnesses They have what one ends up with number one severe polypharmacy number two drugs that interact with each other and number three clearly Drugs that when administered all together are going to have an adverse outcome for the patient So there’s a growing move to begin thinking about patient centered treatment guidelines Taking the particular array of morbidities that the individual patient has and Constructing treatment guidelines around that so I would say keep your ear to the wall for that that’s on the horizon So anyway, this is one rather bleak view of the older patient Whoops what we do here anyway, and another happier view Is that really the the end of life can be a very rich time? so with that I’d be happy to try to take any questions and Answer anything that I said that was quite confusing Thanks I’m sad to report that since the filming of the lecture you just saw, dr Darrell Abernathy has passed away a pancreatic cancer He was a true leader in the field of clinical pharmacology in his leadership will be missed

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