MPP HLD Pharmacology Transcript PDF

okay, so the Focus of today will be highlighting some of these big groups with the biggest one being our statins, right? That's the one that's number eight on our top ten drug list And then we're we're going to refer to most actually all of these at the level of what their class names are Okay So bi...

okay, so the Focus of today will be highlighting some of these big groups with the biggest one being our statins, right? That's the one that's number eight on our top ten drug list And then we're we're going to refer to most actually all of these at the level of what their class names are Okay So bile acids sequester ins that are cholesterol absorption inhibitor. There's only one of those our niacin and fibrates Okay, but the take home here is statins is the go-to therapy unless counter indicated And then the treatment goal if someone is put on statin therapy is a reduction in LDL percentage Okay, and some of these other therapies like niacin fibrates the resins are used to optimize those outcomes that's how to encourage you to think of them is it's like a Toolbox of you will if you will to try to continue to reduce LDL by a percent goal and the Manner which these other drugs are picked are going to be based on individual factors How these drugs work? We will be focused on mechanism of action You'll notice that a table at the end to just help drive home the point will fill that out together of the magnitude of reduction Because by and large statins are going to have the biggest effect And then you might layer on let's say a resin for another five percent reduction to meet that treatment goal for for a patient And As we mentioned Last time the the lipoproteins that are most clinically important That are we we're gonna focus on our LDLs and HDLs VLDLs and chylomicrons are also clinically monitored And they will come up a little bit today as that relates to some of the mechanisms of action of the drugs We're going to discuss but by and large one thing that has stayed Common throughout the field is lowering LDLs. Okay, there has been a bit of a Controversy or just new data has come to light about discrepancies in using HDL numbers based on different races having different predispositions to atherosclerotic diseases This was in the news not too long ago About this good cholesterol may not really be as protective as as we think it is Which is why the emphasis on modulating or bringing down LDL has has remained the mainstay And what we see here is that the name of this study if you want to look it up Density lipoprotein HDLs cholesterol levels with incident of coronary artery disease CAD, right and like a lot of Prominent literature articles and this was in a big journal. They are putting out what is called like visual abstracts, okay, so it's becoming more and more common as a push to engage a public with data and Findings from important peer-reviewed studies. So what we see here might not be able to be interpreted by everybody but more than looking at the primary article and What we're showing here in terms of scientific communication is obviously this this 10-year follow-up. We can see a narrowing of this coronary artery vessel, but what the really take-home here is on the bottom and some of these guidelines that used to be used about HDL Really do not hold up when we look in more diverse populations Very sadly if you look in the bottom left what's plotted here and is color-coordinated is the level of HDL with a CHD events over time Okay, and you see how nicely it's stratified into three distinct groups Right And so what what it's showing there is that those? white individuals that have low levels of H of HDL the good cholesterol so they have too low of level have a higher chance of CHD events Okay, but when we more ethically quite frankly look at populations more representative in the United States and Include black adults in this look at how different that plot is on the bottom, right? Okay this again Underscores the importance of designing all the way back to clinical trials, right? That are more representative of the populations that these therapies are intended to serve And so the advice that clinicians and providers have maybe taken in the past That oh, you know HDL we should really look at as a protective Indicator of the good cholesterol doesn't hold up across all populations. So that is a it is a changing field as As our clinical trials, you know need to be more representative. We're starting to see evidence of this in the literature Which is why we'll continue to focus on LDL in terms of management these The drugs we're going to talk about all have an effect on HDL But let's just keep in mind. We don't know how helpful in terms of cardiovascular Health that is going to be for all populations So back to that big nasty diagram again, we reassured you that you were not going to have to memorize this But we wanted to bring some some clinical significant tools, you know to your attention What I'm highlighting here are the what are considered the four major groups where when we're talking about statin therapy Okay, and one of them relates very much to The individual we we started talking about remember our we didn't give give that gentleman a name But in our case study, right was it his LDL above 200, right? Okay, right. So this alone would actually indicate high intensity statin therapy We use that as kind of a hypothetical to plug in some numbers but in more real-world example, this would be if you got an LDL reading of Greater than than 190 you're going to suggest high intensive Statin therapy and remembering it in high intense statin therapy just means higher dosage. You're using the same kinds of statins For that individual, but they would be on a higher dose compared to an individual that be on a moderate moderate intensive therapy So let's remind us what we do want to take away from this diagram Is Over here. Over here. Okay for our discussion We do want you to walk away understanding these important guidelines and it's just the goals, right? So what does that mean when we're talking about high daily dose? We want to see that the LDL is lowered by 50 percent or greater Okay, that's the goal of high into or what's considered intense therapy where moderate intensive therapy that would be that the Goal would be to lower that LDL by somewhat 30 to 50 percent and this goes back to these these treatment goals Right and trying to achieve them through statin and or other therapies to reach that desired percentage So what I'm showing you here on the left are examples of these statin therapies Wonderfully named they all say statin in them. So you can't go wrong. Yeah Yeah, so the question was how do you did how do how do physicians determine? When lifestyle diet intervention is enough versus I guess you're saying with going right to statin therapy So the gentleman that we discussed that would be right. It would be right to therapy and lifestyle interventions It would be somewhere short of that Age is also a factor a younger individual that does not have any type of genetic predisposition Like familial hypercholesterolemia that we talked about That's when it would be okay, and you could even actually put in to our risk calculator You know It will it will tell you lifestyle intervention and is recommended where therapy is not indicated So when you say primary prevent is very secondary preference, what do you mean? do you mean? Oh Like post myocardial for okay gotcha so we're not gonna get so granular as to If a patient has had an MI or not, what's a better therapy? I think something that will will be occur in our slides. That is pretty powerful Relating to the mechanism of action and its effects statins are so powerful that if someone was put on a statin that had a healthy LDL level it would lower it Okay, it's that that strong its mechanism actually that strong Not necessarily all other of these cholesterol modifying drugs would have that effect What I what I think is good to understand broadly is that there are tons of statins out there and they're going to vary by the Relative percent reduction in cholesterol and then a physician is going to pick which statin for a set individual based on a number of factors Diabetes status is going to be one of them and their its effect on triglycerides liver function is going to be a big one and then relative clearance some Statins are cleared more or less via urine And so if someone has renal impairment, it might preclude them from being on statin therapy or you might select one of the statins that relies less on Renal function for clearance So I wouldn't I like where you're going with the primary secondary But we're gonna get more into MIs myocardial infarctions in January So we're not really going to really go there yet in terms of picking statins. Yeah, Claire Yeah, so it's not that they can't be taken off, okay, it's It's just that it's not recommended to be taken off And I'll get I will actually come back to that when we talk about the four main effects that statins have and There there has been shown and I believe it's a slight increase in risk of stroke due to plaque stabilization Which is why there are some physicians that view statin therapy like If someone's really young they're going to try all these other Lifestyle interventions prior to putting them on statin therapy because Coming on and off statin therapy is not recommended. I believe it's a stroke risk I think that's what it is and as more individuals are and this is where it gets into a lot of medicines a lot of gray There's studies out there us when to prescribe prescribe statins is controversial and as we said last time it's going to very cardiologists to cardiologists As to when in their scope of practice they might start statins But well as we see an increase in the amount of statins prescribed We're also seeing when you have more people taking stands. You're going to see more adverse effects, which is why It's a bit of a moving target But I think it's good to know since we're covering it what what's out there because it's it is very varied Okay So the groups that we're covering here are in blue that's on the level of the the classes of drugs So let's start with that big one which we we hinted at the main mechanism of action of statins Right, so you should be able to recognize any statin we throw at you a tour of a statin for example is the big one and have the word statin in it, right and it's What it what stands are are the those hmg CoA reductase inhibitors and they've shown time and time again to substantially reduce the risk of coronary events and death from a cardiovascular coronary heart disease They are considered those first line First line treatment for patients with that elevated risk, okay They are There are definitely very strong counter indications that we're going to touch on one of them being being pregnancy another one being liver function because It is extensively metabolized by the liver This is the kind of drug that in addition to running that liver. Sorry liver panel running the lipid panel oftentimes at that point they're going to also be checking liver enzymes because If you do not have healthy hepatic function statins are not going to be an option for that patient But back to clears a question about You know, why why might you be on them or why might some physicians within their scope of practice? Not take someone off a statin and let's let's zoom in on these therapeutic benefits, right? We talked about statins last time as you know, the their main mechanism action is that they're going to Inhibit that enzyme. What does that enzyme do? Remember? What does hmg CoA reductase do? Okay, it is it is the main enzyme or the rate limiting step Enzyme involved in cholesterol synthesis. Enzyme involved in cholesterol synthesis. So if we inhibit it, right, we're not going to be making cholesterol All right but that has a Domino effect if you will right so if there is going to be and where what tissue are we talking about? We're when we're talking about this hmg CoA reductase Just make sure we're all on the same page liver. Yes, we're talking about in the liver. Okay, so If the liver now is making less cholesterol, what is a downstream effect of that? Yeah, it's a bit louder It tips the balance and say that we need to bring more cholesterol in From the blood because we're not making we're not able to synthesize cholesterol So that increases the expression in Receptors our LDL receptor LDL or LDL receptor Okay, so with that increase in LDL receptor expression, right? Okay, so with that increase in LDL receptor expression, right? We're now going to catch Extra or any LDL in the vasculature and bring it into the liver When it's in the liver, what's going to happen? to that cholesterol It's good Okay. Yep. So when we have too much of it, right because we're trying to treat hypercholesterolemia And we've got an increase in LDL receptor. Generally, it's gonna break it down Okay, so you you're gonna bring cholesterol Or take it out if you will of the vasculature and break it down in the liver Okay, one of the reasons we're going back over this because there's a couple drugs that relate to this mechanism of action of breaking cholesterol down liver Okay, the therapeutic benefits that we have highlighted here. Okay, so Let's talk briefly about these okay, so it's not that Statins minimize plaque, okay, there's not really a therapy out there that Takes away the plaques that are already there But one thing to improve the health of the vasculature would be to stabilize those plaques Right because as they break off what could happen plaques break off what happens? Yeah, yeah, we're gonna deal with Anything from a pulmonary embolism? It's gonna cause a myocardial infarction right an ischemic event, right? So it's very dangerous to so you might see well, why do we want to stabilize the plaque? It's we want to stabilize it. So none of it causes a thrum thrombus And Then we're going to improve it improves coronary endothelial function We're not going to go over the how of this, but I do want to connect it to why that's important okay, remember when we talked about foam cells and atherosclerosis and That there causes generalized endothelial dysfunction, right? That's when we have then more reactive oxygen species and we have LDL starting to migrate where they don't belong because there's actually a Thinner layer of the endothelium to which they can migrate into and become foam cells Well longer therapy with statins tends to help improve that endothelium endothelial function Along with stabilizing the plaque it's going to inhibit platelet thrombus formation and Generally have an anti-inflammatory activity, right? And when we talked about that those foam cells, that's essentially what's happening there. These is little local inflammatory response that leads to a state of vessel atherosclerosis And here's the point that I had mentioned earlier Statins are so strong and so powerful that it's going to lower the LDL of an individual with a healthy level of LDL Okay, so it doesn't these this these drugs class of drugs doesn't just work in in individuals that have elevated LDL Okay, so I know that looks like a lot of blue but remember you see statin it's a statin whether it says pit of a statin Loa statin a torvus statin simba statin fluvastatin. They're all stands. Yes They're usually big they're usually appears to be a threshold. So this gets back to having adding some other therapies an LDL Wilk, I'm sorry. Not LDL statin will Find will reduce it by a certain percentage. It's usually a range because it varies by individuals There are some individuals that for no known reason they are not responsive to statin therapy And we don't understand why There are some individuals that may all start with you compare two individuals that both have LDL 200 But for one patient it reduces Reduces by 30% and another patient only 15% that that gray that you just have to help manage clinically Okay, so we saw this diagram before one thing. I wanted to clarify is we really aren't going to go through this fourth point here, okay, it does statins do minimize the The Synthesis of V LDLs and V LDLs are really the precursor of LDLs But that really is not something we focused on So really when going back to this diagram focus on one two and three in terms of that Domino Effect of statins. We are going to talk about modulating V LDL, but that's via another drug that we'll talk about I'm gonna just double-check that we have already stated everything on here. I Think let's see Yep All right. So here's that arsenal I was mentioning of statins. Okay, let's first put a big FYI on these numbers Okay, what we wanted to clarify here is just back to relates to forget who asked the question Let's just eyeball some of the differences here right in terms of the anticipated Serum reduction of LDL. So this is where individualized, you know clinical management of these numbers and the selection process of which statin is going to be driven by Physician and lipid panel and other factors contributing to that patient's general health The other the other things that we mentioned here is some more or sorry That would be less less or more rely on the percentage that needs to be excreted via the kidneys and so The kind of three big things to keep in mind with statins our liver function Cannot be used during pregnancy and you know renal function being one of the third parameters and So we mentioned the these adverse effects because statins are so prominent we don't do adverse effects for all drugs but What can happen because statins are Metabolized exclusively in the liver it can elevate liver enzymes And this needs to be monitored. Okay, so Which is very easily done because back to that clinical management of your patients are going to be coming back in somewhere in the order of Four to twelve weeks to check that lipid panel at which time you would be looking at their liver enzymes as well Making sure they're not too high In addition to seeing how far down or how reduced their LDLs are And so because of this, that's why liver function must be checked prior to prescribing a statin therapy One of the other ones that I'll mention is generalized muscle pain and weakness The the mechanism this isn't really Worked out But it can it can cause someone to feel so Fatigue that you would move on from from statin therapy or have such, you know adverse muscle pain That you would seek a different form of therapy So the question is specifically with statins Do the the do those adverse effects persist? so the biggest one is muscle pain and muscle weakness and That is enough that it doesn't tend to subside for those that experience it now It's not super super common either But those that do it often can be the reason why they move away from statin therapy Or they move to a different you saw how many we have they move to one that might induce less muscle pain So So the question is if someone's drinking alcohol while on statins, yeah, so because of the It's gonna depend on the amount of consumption and if that changes over time like a sudden alcohol binge versus someone that Consistently drinks a certain number of alcohol beverages, you know per week That's a bit outside of a scope, but I know where you're getting with with liver function But that's that's going to vary by individual. What would be most dangerous is someone that is self reports as a non drinking patient is put on a statin therapy and then they their alcohol consumption really increases and that's where this clinical management with statins and Re-checking that lipid panel and having those conversations with that patient would be so important Okay, our next Class would be inhibitors of cholesterol absorption. And as we go through these next Drugs, we're going to relate them to some of the normal cholesterol physiology Okay, and how it's simply manipulated By these other drugs with the context that the other drugs we mentioned from here on out are Oftentimes used in combination with statins to meet those goals. Okay, so these Inhibitors of cholesterol absorption are going to be The the name of the group widely are called niacin We see them over here on our diagram. All right, but let's first look normally what happens. So in Fat tissue here triglycerides are going to Be made into fatty acids or free fatty acids, which will then Target the liver for the eventual production of V LDLs Remember how we said V LDLs are like the precursor to LDLs So this normal flow process here is fatty acids coming from adipose Tissue are going to then be used by the liver to make V LDLs and then eventually make LDLs The reason why it's grayed out is when we use cholesterol Inhibitors of cholesterol absorption like niacin It's going to inhibit the conversion of triglycerides to fatty acids. Okay, so when when Triglycerides in the fatty acids, sorry when we cannot make fatty acids in the adipose tissue That makes them less available in the liver, which means they're going to be eventually going to be less LDLs being made Let's see if I cover that so With with niacin's we're typically going to see just about a 10 to 20 percent reduction Okay, because there's a range you don't need to memorize. We're gonna throw a couple of these percentages out there Okay, it's going to be helpful to understand general magnitude But the effect is going to vary. Okay, and we'll try to drive that home in our in our last table So because the mechanism of action is wholly different right than statins This is a nut. This is a candidate that can be used very safely with statins It does lower triglycerides But but that is not a focus of what we we are going to be Talking about in in detail What they are more commonly known for and as we mentioned the beginning of class this outcome is is varying is They are most effective for increasing HDLs And the thought process here being when you don't have a lot of LDLs The body is going to compensate by making more HDLs Which now we're having evidence of that effect is going to vary across different races This might be more cardio protective for some individuals rather than others So when you think niacin want to think mechanism of action We're gonna be making less LDLs by inhibiting the production of fatty acids in adipose tissue Which will make less LDLs, but also increase HDLs Now let's go over the fibrates the fibrates which Are include phenofibrate? Gem from Gemfribrozil are going to be P par alpha activators and What? P par alpha you hear P par alpha. P par alpha you hear P par alpha. What do you tend to think about with P par alpha? Anything come to mind? Anything come to mind? I don't have something specific in mind I just wanted to see so sometimes students have heard of P par alpha sometimes they haven't nope, okay So let's make a little note that this is good. This is a transcript P par alpha is a transcription factor Okay, I know you know what that is Okay and a transcription factor if we're going to Increase the product fibrates increase the activation of P par alpha This is going to have a whole host of effects right because we're going to increase the Transcription of this the transcription factors target genes this effect or will have will be twofold I'm gonna highlight the part you need to know so it's going to increase plasma HDL It does that by increasing a pick a P. Oh a P Apoprotein a one and apoprotein a two remember these are the proteins on the surface of Lipoproteins that can be used to identify the kind of lipoprotein and the other big one is that it helps decrease plasma triglycerides So This one what makes this one unique you see we don't mention LDLs right this one this fibrates their main mechanism of action doesn't have a huge effect like statins do on LDLs They're mainly used to lower triglycerides and Increase HDLs by activating the transcription factor P par alpha Think I've now said these bullet points, but let's make sure yep, okay Let's go on to the resins which has a different target. Okay, this is bile acids Okay, something we haven't we haven't talked about But I would encourage you to think of resins as almost like a sponge a bile acid sponge Which elicits a reaction by the body? To help treat hypercholesterolemia So if we look on the left, okay in the liver when we give bile acid sequesterance They are going to be in the small intestine And they're going to bind bile acids and cause them to be excreted in the feces Okay, this effect elicits LDL lowering effect in the body and this is how normally in the liver when we have Cholesterol can be further broken down into Bile acids and there's just normally secreted some secreted in small intestine and some gets reabsorbed back into the liver But when we start ingesting these Resins, they're going to bind up in the small intestine as bile acids are being Secreted from the liver in into the small intestine. They form a complex They're like a sponge like I said, and that's going to cause them to be excreted. So we're tipping the balance a favor There's less bile acids coming back to the liver So when this happens the liver is going to start pulling in more Cholesterol in the form of LDL from the vasculature We're having similar effects, but we're modulating different aspects of this cholesterol system to try to lower cholesterol So resins are a LDL lowering therapy Not nearly of course as strong as statins But are going to be used to achieve those therapy goals in terms of percentages Because what's going to happen as the Cholesterol starts is more cholesterol gets pulled into the liver We're going to also start to see an increase in LDL expression as there's as as the amount of cholesterol in the in the liver increases so this will cause a Continued increase that up regulation of LDL receptors will further the amount of LDL is being pulled from the vasculature and into the liver This can also be used very safely with the two with the drugs We just mentioned okay very different mechanisms of action can be used safely in combination All right, we introduced this drug last time as targeting the neem and pick like channel in the small intestine So now we're in the small intestine. This one does not directly In in terms of its mechanism of action where it targets it targets a small intestine And it does this simply by letting less LDL be be absorbed by inhibiting this neem and pick like protein or a channel I should say and so it's capable of reducing cholesterol so somewhere in that order of about 17% and Because we're targeting a very specific channel in the small intestine can be used safely with many other LDL lowering therapies We've gone through this one Now let's just mention that combination therapy is simply taking two or more of these Anti-hyperlipidemic drugs to try to control the mostly LDL level in in the blood The most common would be our statins and our resins used together In fact, they have recently been used in combination in one pill that has come to market so it's It just helps with adherence any time a patient can take one pill rather than two pills safely It's you're going to have a higher level of compliance and more likely to reach that goal So this came to the market just a few years ago. You don't need to know the name Rosa set I just want you to be aware of This is a sorry a newer combination. This is statins and Our Neiman pick like protein inhibitor as Tima Mabe and they are now a new oral combination therapy and Claims to reduce it by soups up to 72% So this would be someone that with it is coming in with very very very severe Hypercholesterolemia that would need a reduction by 72%