Mpp Antiplatelet Pharmacology Transcript PDF

All right, so let's talk about anti-platelet pharmacology today. So really the goal of today is to understand how we go from these lovely little round platelets into this like splattering platelet, which is here, so this is an electron micrograph of an inactivated platelet and then the activation pr...

All right, so let's talk about anti-platelet pharmacology today. So really the goal of today is to understand how we go from these lovely little round platelets into this like splattering platelet, which is here, so this is an electron micrograph of an inactivated platelet and then the activation process, which is going to be the bulk of the physiology that we talk about, and then obviously the pharmacology is preventing this thing from happening, so that way you don't have things like heart attacks and strokes that occur. My objectives are listed here for you. I would pay attention to the markers that I identify in number one as well as the markers in number five specifically, as these are going to be the ones that I will focus on when it comes to questions related to predict what would happen if you gave this drug, would levels of this increase or decrease, these are the ones to be able to recognize their roles of. But let's go ahead and jump in. I have tried my best to kind of color code where these drugs work throughout the presentation, so that way you can follow on different slides exactly what steps are being inhibited by what. I tried also to only pick one drug out of each drug class to be aware of, so that's what we're going to do is we're really just going to focus on one of each instead of kind of learn every single drug that exists because there's tons of anti- platelets and that's what we're looking for, but for now as far as just understanding the basic mechanisms, I think this is more than enough for us to spend our time with today. The next couple of slides are just overviews for you. I'm not going to talk through them, but if you're like, I just need to see this written a different way, these are all really helpful, and then we will be going through all of these diagrams, so if you understand the diagrams, you will know this material quite well. So last time I said know the table, this time I'm going to say know the diagrams. That's going to be your key to success on these lectures. So last time, obviously, we talked about the fibrin-rich clots in lecture 27, so today we are shifting that and we're going to talk about the platelet-rich clots. So this is what's going to happen with things like heart attacks and stroke, and you guys have had or are going to have cholesterol synthesis next, Dr. Hum, next. Okay, so when we talk about cholesterol, cholesterol can deposit on the walls of arteries, and when those plaques shear off, they expose the collagen underneath, and that's when this cascade of platelet formation starts. So we're really going to start with what should be happening in normal healthy tissue, and we are going to walk ourself from 0.1 all the way to 0.9, we're going to walk ourself all the way through this diagram, because this diagram is honestly the best diagram I've ever seen. I tried to find a different one that was less busy, but honestly, this one is so good. I just don't think that there's any better way to do it than to go through what Golan does in their textbook and walk you guys through each step of this. But the three main steps to be aware of are the adhesion, which is the initialization of this where platelets stick to the collagen, then those platelets will release out messengers to recruit other platelets, that's through the granule release, and then those other platelets will come and aggregate and consolidate. So those are the three broad overviews of forming the platelet plug that we are going to focus on. But what is happening normally, okay? So this is what should be occurring. We have those lovely round platelets here in blue that are, you know, just rolling around your blood, and you have this healthy intact endothelial cells of your vessel that are hiding this collagen layer underneath. No collagen exposure, no platelet activation is kind of the idea. You see collagen, you are now immediately going to have things start to stick. This is why if you cut yourself putting cotton ***** or cotton swabs or cotton on a band-aid or cotton tissue paper is all beneficial to stopping it. What is cotton? Collagen. So you are doing that same thing in order to create hemostasis when you do that. But ideally we have no collagen fibers exposed. And so the reason that's happening is twofold. A, collagen is what is going to stimulate it, but also those healthy intact endothelial cells are releasing natural substances, namely nitric oxide and prostacycline, that work to stimulate the conversion of ATP to cyclic AMP. More cyclic AMP means less calcium available to degranulate these cells. Cyclic AMP, if we can increase those levels, would be a really good therapeutic target. So if the issue is that we are getting more ATP created, could we prevent that degradation so that way that could be a therapeutic target? Absolutely. So we'll talk about that for one of these drugs. But so this is what's happening in normal healthy tissue. We have collagen that's hidden, so we have nothing to be exposed, and we have nitric oxide, which serves as a vasodilator, and to inhibit the process of platelets sticking together. So then we get into what happens when we have these endothelial cells rupture off. And so now we have this break in endothelial cells, and now we have that collagen fibers exposed. This is going to be step one of formation of the platelet plug to plug this hole, because right now, if we can see through this endothelial cell, we therefore also will have blood spilling out of it, right, or endothelial is what's holding that blood inside the vessels. And so if this is not intact, blood is now going out. We are bleeding either internally or externally at this point. So we want to quickly stop this from happening, because that is bad. So the way that this happens, if we look at the details of what is going on here, this is kind of like a very zoomed-in photo of what's going on right here, okay? There are two main molecules to note. A lot of them are going to be glycoproteins, and they all have different initials. There's 2B, 3A, 1B, and 6. So make sure that you keep your glycoproteins straight when we're talking about them. So here's what's happening first, is we have von Willebrand factor. This is going to be secreted by both activated platelets and exposed collagen. So when that collagen gets exposed, it is going to be the first thing that releases von Willebrand factor, and that von Willebrand factor is right here on this diagram. It is this thing that is adhering to the collagen. So it sticks to the collagen, and then it binds glycoprotein 1B, which exists on the, oh boy, the platelet itself. So this glycoprotein 1B von Willebrand factor collagen interaction is critical to initiation of this process, because this is what is anchoring the platelets to the exposed collagen. Glycoprotein 6 is also involved, and it is basically here as a support, because if you think about it, if I stand on one leg, I'm wobbly, right? Like I can easily fall over. If I'm standing on two legs, I am firmly planted now where I'm at, which is exactly what we have here. We have leg 1, which is the collagen von Willebrand glycoprotein 1B, and we have leg 2, which is that GP glycoprotein 6. Glycoprotein 6 is also on the surface of platelets, and it interacts with collagen, as I mentioned. So there are two main interactions that are starting that process of platelet adhesion and sticking it to the exposed collagen. So from there, we've now got this process initiated. We have a platelet sticking where we want it. What comes next? Well, that platelet starts to become activated, and it starts to release its intracellular contents via exocytosis, and it releases secretory granules. And those granules basically potentiate this response and get other platelets recruited to the area, which is why activated platelets secrete von Willebrand factor, to get more of them anchored to that basement membrane, and it releases other stuff as well. Click, please. And then by releasing those other things, that's what's going to cause all those platelets to aggregate. I feel like a slide did not go, and I'm very confused. Do you guys have an extra slide here? Okay, for some reason, I think they got out of order a little bit on my thing, because I meant to show you guys what all is released during the granule release first. So, when we talk about what's released, we have things like thromboxane A2, ADP, and serotonin. These become big key mediators, and those create this feed- forward loop that potentiate the aggregation and consolidation of these platelets. Now, we will walk through how exactly that works, but essentially, these mediators are released, which starts to stimulate this interaction between your GP2B and 3A in fibrinogen, and this is the molecule that starts to link these platelets together. So we have the glycoprotein 1B von Willebrand factor and collagen interaction that's adhering it to the basement membrane, but then this GP2B3A fibrinogen, GP2B3A interaction, and is what's starting to link them together. Fibrinogen, does anyone remember where fibrinogen came from? That was part of that clotting cascade that we did on Monday. It's the very end or factor like 1. So there is this interaction between the clotting cascade and the platelet cascade, and I don't want to dive too deep into that, but there is this cross talk that's going on between the two, and molecules from one can start to stimulate the other, so all of these clots are going to have components of both the clotting cascade and the platelets. It's just fibrin-rich clots have way more fibrin, and platelet-rich clots, which is what we're talking about today, have way more platelets. All right, so let's jump into these markers, and you can see all of these different areas aspirin is going to inhibit. Here we have ADP inhibitors, we have GP2B3A inhibitors, and we have something way back here that we'll talk about as well. So these boxes are different therapeutic targets for how to inhibit this process, because this is all well and good if you want to stop bleeding, but if you're not really bleeding, you just have this collagen exposed, and you're quickly forming this rapid platelet plug, it can quickly grow too large, and when you have these very small vessels, like the vessels around your heart, they can quickly form a platelet plug that pretty much blocks the causes you to have symptoms of a heart attack. So let's focus on granule release, jumping back into how exactly that's happening. There are a lot of things being released. The main players I want you to recognize are the fact that ADP and collagen specifically activate phospholipase A2. When we start talking about the arachidonic acid pathway, this becomes incredibly important, because this is the first step of liberating arachidonic acid and converting it into molecular signals that ultimately cause this interaction between glycoprotein 2B and 3A. So the arachidonic acid pathway is going to be key, especially when we're talking about the function of aspirin, into potentially inhibiting this step. So arachidonic acid is converted into, big key mediator to know, thromboxane A2. That conversion happens via an enzyme known as cyclooxygenase 1 or cox 1. Big therapeutic target to know, cox 1. This is what aspirin is going to target, is cox 1. Thromboxane A2's whole purpose is to help start this activation process and make those platelets sticky and start adhering to one another. And so then you get this release of ADP, calcium, serotonin, and other things that again just start to create this feed forward loop that encourages both more platelets to adhere to the basement membrane and more platelets to adhere to each other, because remember the first step up here that was released was caused by ADP, which is also released down here. Whenever you have a secretory process in the body, the majority of the time it's going to be a calcium dependent process. So calcium plays a key role. Calcium plays a key role. Calcium plays a key role in ensuring the release of these granules. And so that becomes just something to note whenever we're talking about secretory release of items, when exocytosis is almost always a calcium driven process. There are a few exceptions to that, where there is direct mechanical exocytosis, but predominantly any time we're talking about release of stuff, I would have calcium in the back of your mind as what is responsible for that, okay? We're going to dive into these two photos in detail. And this is where Dr. Fuchs's foundational lecture of how does cellular signaling work becomes really important, because all we have here are G-coupled proteins. All this is is just a bunch of G-coupled protein signaling. You guys have done G-coupled protein signals before and other things. The only question here really is what starts the process and what is the ending part of it? The middle always stays the same really when you're talking about G-coupled proteins. So let's start first up here. I mentioned we have arachidonic acid. Arachidonic acid gets liberated by phospholipase A2, and that arachidonic acid gets converted via cyclooxygenase into thromboxane. That is important because thromboxane is going to act on the thromboxane A2 receptor, okay? Acts on this receptor, which is a G-coupled protein. It is going to work to activate phospholipase C. Phospholipase C will ultimately activate phosphokinase C as well as increase those cytosolic calcium concentrations, ultimately leading to the exocytosis of these granules. It will also activate more phospholipase A2, which again will feed forward and liberate that arachidonic acid, so that way this is our feed-forward mechanism for having all of this keep occurring because phospholipase A2 is what started this whole process in liberating arachidonic acid. Ultimately, what happens through this G-coupled protein is we get the activation of this GP2B3A receptor, and that's the whole goal of aspirin – sorry, the whole goal of thromboxane acting on the platelet. Really the goal is to stimulate the thromboxane receptor, which then leads to the activation of this receptor, because this is the receptor that's going to go out and grab other platelets. So we can either inhibit up here or we can inhibit down here. Those are kind of our two big targets. Inhibiting things in here – you guys have talked about other pathways that involve DAG and IP3 and all that, right? Targeting those pathways aren't very specific. You're going to catch a lot of other things that your body has to do because we use the same signaling mechanisms. So big targets for drugs are almost always at the beginning of the cascade and then at the end of the cascade. That's a good rule of thumb for a lot of intracellular signaling issues, with the exception of very specific chemotherapy that you guys talked about and where you may want to inhibit those in those, like, JAK stat pathways. The other key player in this is ADP, adenosine diphosphate. And it binds to what's known as the P2Y12 or the P2YADP receptor. It's listed as both things, depending on which textbook you read. And ADP is going to act on this G-inhibitory protein. And that inhibitory protein is going to inhibit adenylcyclase from cyclizing ATP, because remember, cyclic AMP's job was to prevent all this from happening. So if we can prevent ATP from being converted to cyclic AMP, we can keep potentiating this activity. The other thing it does is it acts on a separate receptor that is GQ-coupled and is the same phospholipase C that we see over here. So it's doing the exact same thing on this side of the equation as it is over here. So it's giving you two mechanisms. A, it's stopping the inhibitory portion of it. And B, it's signaling the stimulatory portion to ultimately create that GP2B3A receptor. My recommendation is to spend some time walking through this process and talking through it out loud. Think about if collagen was exposed, what would happen to intracellular levels of phosphokinase activity? If I gave a drug, what would happen to the activity levels of XYZ? That is a good way of thinking through the physiology of these processes. But again, this whole right side kind of jumps very quickly, because all it is is it's this exact same pathway that's over here. It's just mediated by a different receptor. And we see this a lot of times. Your body creates these redundancies. There's actually three different receptors, both thromboxane, thrombin, which comes from that clotting cascade pathway, as well as ADP all stimulate the same GQ-coupled receptor. Because we want to have a lot of redundancies because bleeding to death is very problematic. So we want to make sure if we sense that we are bleeding, that we have some way of initiating this process. Questions about these two diagrams in intracellular signaling? All right. If we look at drug targets to put it in perspective, as we go through the drugs, these are the areas that we can target in terms of our therapy. And so we're going to talk about aspirin and how it works. We'll talk about GP2B3A inhibitors. We'll talk about P2Y12 inhibitors. And then we have this enzyme down here, phosphodiesterase. Phosphodiesterase's job is to break down cyclic AMP into other products. We said that cyclic AMP, though, is what's going to inhibit these platelets from becoming active. So if we want to stop this excess clot production, increasing cyclic AMP levels becomes a really good thing to do. I mentioned that we could do it by inhibiting this up here, but we can also do it by inhibiting the breakdown of cyclic AMP. And so phosphodiesterase is the enzyme responsible for breaking down cyclic AMP and then starting the process back over with the non-cyclinated form of AMP. We will put all the drugs in the context here in a few slides. But before we talk about the drugs, I think it's helpful to visualize where they are at in the process so that way, when we're talking about them, we can talk about them in a little bit more detail. The last part of this, basically, is that all of that becomes sticky together. We get fibrin tangled in here and fibrinogen. This portion, basically from here on up, you don't really need to know. This is just the finalization of those clots forming and creating the platelet plug. And then as we talked about in the last lecture, TPA is still the same thing that starts to break these down. So that's why for patients who have a really bad heart attack and we can't do other interventional techniques, TPA is listed as a possible therapy because TPA will lead to the breakdown of both fibrin- derived clots and platelet-derived clots. But really, one through seven are the big portions to know from a physiology standpoint in how this is working. This is in the textbook. I've got it cited at the beginning of the chapter. The textbook does a nice job walking you through it. So if you want to refer to that, I hate saying, you know, go to the textbook. But honestly, this is one of those where it just takes a couple times of walking through it to really understand it. Pay attention to the markers that I've highlighted in the objectives and then exactly what is causing these interactions, whether it be von Willebrand factor in which glycoprotein. The glycoproteins are all just numbered differently. I would expect to see questions where multiple glycoproteins are listed with different numbers, right? That sounds like a very easy way of potentially testing people on their knowledge of how this physiology works. Hint, hint, nudge, nudge. All right. So let's start talking about this broad group of drugs that we have available to us. And so I'm going to keep separating them based off of these colors. We'll talk about our COX-1 inhibitor, which is going to be aspirin. We will talk about two different P2Y12 inhibitors because they work slightly differently. We will talk about two different GP2B3A inhibitors because they work slightly differently. And we will talk about one phosphodiesterase inhibitor. Now, of note, there is one objective on here that is designed to prepare anyone who's thinking about going to pharmacy school. That objective states to recognize the structure of clopidogrel in its active form. So I know that most of you are probably planning to go to medical school, but because this program preps people for multiple different health professions, there is one Med Chem thing to know, and I'll highlight that when we get there because it's very foundational into how clopidogrel works. I only include one question because, honestly, I hated Med Chem all the way through pharmacy school. So I'm not going to punish you guys with a bunch of Med Chem, but I do think it's going to be exposed to it to kind of understand what would life be like if I want to become a pharmacist in the future. What does that schooling look like? So this is another opportunity to include that in our lectures. So thank you again, Dr. Hum, for having me. So let's talk about the arachidonic acid pathway in a little bit more detail. So where do we get arachidonic acid from? Really, we have our membrane phospholipids, and that is where arachidonic acid is going to be liberated from. That phospholipase A2 that I mentioned, when I keep saying it's liberating it, it's basically allowing these phospholipids to come off on the basement membrane into becoming free arachidonic acid. Arachidonic acid then has two different ways that it can be converted. We can either go through the cyclooxygenase pathway or COX, or not pertinent for this lecture, but very pertinent for asthma is the LOX pathway. When we get the formation of leukotrienes, this is what causes us to have a lot of various asthmatic responses. So I want to point that out because there's one side effect that does become pertinent too. But really COX is going to be the big one. So if we prevent arachidonic acid from going through the COX pathway, we can prevent the formation of thromboxane, and that prevents thromboxane from binding to the thromboxane receptor, and ultimately prevents that whole GQ-coupled protein signaling that starts to expose the GP2B3A receptor. So aspirin does this irreversibly. That is incredibly important to the mechanism of aspirin. It does this through a acetylation of a serine residue. You don't have to know this for the exam, but this is why OCHEM is so important to getting into these various schools, is on here, there is an OH residue. There are free electrons here. These electrons go up, and they attack this carbon. These electrons go up. These electrons go down. These electrons fold in, and that's what gives us the salicylic acid. And why this binds irreversibly. Most of the time when we're talking about drugs, they're drugs that just sit there in the receptor, right? They just are held there together by things like van der Waals forces, and are just kind of sitting there, and then at some point they will dissociate from those receptors and go on their merry way. Aspirin is totally different. It permanently changes COX-1. That is so important because platelets don't have nucleuses. Platelets can't make more COX-1 to fix this problem. If you were to do this with a reversible inhibitor, things like ibuprofen, you will, in the short term, potentially stop your risk of bleeding. I mean, increase your risk of bleeding, but then once it goes away, you're at risk for having a heart attack. This is why people who take a lot of NSAIDs and have significant cardiovascular disease tend to have MIs between 3 and 7 a.m. Because whatever NSA that they've taken that is reversible has disassociated from that receptor, and now they're at an increased risk of having platelet activation because they're no longer inhibiting it. So using an irreversible inhibitor is essential to the function of aspirin. Because of that, once you use it, those platelets are inhibited for the life of the platelet, which is about 28 days. So we use this in patients who have had a heart attack or a stroke before in order to prevent future ones from occurring. Basically, all patients who have had a heart attack, nearly all patients who have had an ischemic stroke are going to be placed on aspirin in order to prevent further clot formations from occurring. In a lot of these patients that have MIs, they will get a stent put in. And I mentioned last time that anything that's artificial in the body and is metal is very sticky. Platelets love to stick to artificial things. So after we put in something artificial like a stent, we will also start them on aspirin as well as some other drugs because the risk of clotting off this metal is incredibly high. We put in an artificial knee. We give patients aspirin to keep blood clots from forming. We put in an artificial hip. We give platelets aspirin to keep blood clots from forming. We put in an artificial valve. Again, we give platelets aspirin because of that risk of clotting is so great. So adverse effects to know about this, I want you guys to think of GI bleed specifically. While bleeding anywhere is possible, the arachidonic acid pathway is also responsible for the production of prostaglandin E2, which if you have the pleasure of joining our program, you will listen to Dr. Hum and her musical selections as she goes through why prostaglandin E2 is important. Prostaglandin E2 does a couple things, but the one to know for this lecture is it protects the stomach. So if you block COX enzyme, you will decrease the amount of PGE2 available, making the stomach more prone to being harmed by gastric acid. So that's why GI bleeding and ulcer formation is so big. The other thing is you're at increased risk of asthma exacerbations. If we block that COX pathway, all of the arachidonic acid has to get converted to something. If it's not going through COX, it is then therefore going through the LOX pathway on the other side of that diagram. And I mentioned that that is what causes those asthma-like symptoms. So it makes sense that if we block half of that pathway, everything's going to be shunted to the other path. So the adverse effects of aspirin are incredibly predictable based off the pharmacology of how they work in inhibiting this arachidonic acid pathway. It is available in two forms, one as a regular oral tablet and one as an enteric-coated tablet. The purpose of that enteric coding is so that way it's not released in the stomach. If we can make it so that way the aspirin is actually released in the small intestine, that risk of GI ulcers is dramatically decreased because you don't have any aspirin directly inhibiting prostaglandin E2 at the site of action. If you're having a heart attack though, do you want to wait for gastric emptying to occur and for it to get into your small intestine and start to be released? Absolutely not. This is why we tell people to chew baby aspirin when they're having a heart attack. If you have the regular tablets, it doesn't matter if you chew it or not. But most baby aspirin are enteric-coated and so we tell you to chew it so that way you break up that enteric coding because then it's no longer protected and can be absorbed in the gut and act really rapidly. So that's the mechanism behind why we give an enteric-coated product in general but why that same enteric-coated product is potentially problematic when talking about patients who are actively having a heart attack. Questions about aspirin? So that's really stopping the top of that GQ-coupled protein receptor on the left side for the thromboxane A2 receptor. Clopidogrel has a similar mechanism of action in that it binds irreversibly to its receptor. It's just that this time the receptor is going to be the ADP receptor instead of that cox enzyme. You'll notice that it does this by binding at a cysteine residue. Aspirinida at a serine residue. Clopidogrel does it at a cysteine residue. And it does that because cysteine has sulfur and we create this disulfide bond that ultimately adheres it to the receptor itself. So this is what I mean by recognizing the structure of clopidogrel in its active form in that objective. This is how clopidogrel normally exists. We have this cyclic ring structure over here and this is where our sulfur is which is going to be what creates this disulfide bond. Because it's a prodrug, it gets activated by CYP2C19. So if you're on something that inhibits 2C19, is this a good drug to take? No, because it's not going to work. If you are genetically predisposed to being a poor metabolizer of CYP2C19, is this a good drug to take? No. If you are a hypermetabolizer of CYP2C19, you can take it but you're probably at an increased risk of bleeding because more is going to become active. So it gets converted into this intermediate metabolite which also goes through conversion by CYP2C19 into the active metabolite which is what frees up this sulfur to make it so that way it can form this disulfide bond. Seeing this not in the ring form is what lets you know you have the active form of clopidogrel. This is what then ultimately binds to that cysteine residue and creates that disulfide bond. We use this very similarly to how we use aspirin. We give it to people after they've had an MIR stroke and we give it to people after we've put in a synthetic material in their body like a stent which is what we do during percutaneous coronary intervention. So the indications are very, very similar. Again, the adverse effect is going to be bleeding but I want you to recognize the role that CYP2C19 plays in activating this because there's certainly an increased risk of treatment failure in patients who are poor metabolizers or who are on those CYP2C19 inhibitors and certainly an increased risk of bleeding if they're a hypermetabolizer because they will generate more of the active metabolite. This is also available orally. The other option that we have is ticagrelor. In ticagrelor, basically here's adenosine. We've basically taken adenosine and we've kind of modified it so that way this will bind to the receptor. It doesn't do it irreversibly. It just kind of sits in the receptor so it's reversible but it's basically a mimicker of adenosine. So that's why it works to inhibit the adenosine receptor. We use this for the same thing that we use clopidogrel for. Some clinicians prefer clopidogrel. Some prefer ticagrelor. There's really not a definitive reason behind one or two. If you have someone who's on CYP2C19 inhibitors though, ticagrelor would certainly be preferred because it's working the same way but doesn't have that nasty possibility of treatment failure for patients that are on CYP2C19 inhibitors. Really no interesting adverse effects to know for this and it is also available orally. So, so far we've talked about a bunch of things that can be given orally. Are our patients always conscious and able to take oral drugs? No. So what do we do for the patient who can't take an oral drug or maybe has a contraindication for one reason or another to these drug classes? We have to come up with something that is available intravenously. And that is where the GP2B3A receptors come into play. We have two of them. One of them is absciximab because it ends in mab it must be a monoclonal antibody good and it inactivates GP2B3A by basically binding to it and preventing it from interacting with fibrinogen. So it's basically going to insert itself here and hold on to it and it doesn't allow this linkage to occur. We use this in one and one specific instance only because it's IV. We give it while we are actually putting in that stent. So during that procedure, if they haven't received something orally beforehand, we can give this to them as an IV during the procedure to prevent blood clots from forming while we do the procedure. It has a very short half-life so once we turn it off, we hopefully need to get them back so that way they can take oral medications and we will switch them to something else. But during that procedure, this is an option for patients who haven't gotten an oral P2Y12 inhibitor beforehand. No interesting adverse effects to note. Just know that it's available IV. So if I have a patient who can't take things by mouth, this becomes one option. Our other option is my favorite drug in the whole world to say, F2-fibatide. Say it with me. F2-fibatide. It's one of the hardest ones, but it looks just like it sounds. F2-fibatide. F2- fibatide binds to fibrinogen. So that is going to be kind of how it's working. Again, it technically binds to an inactive HGP2B3A, but it's basically pretending to be fibrinogen and interact with it. Again, it does this reversibly. It is not a monoclonal antibody, so it is much better tolerated. Monoclonal antibodies, especially chimeric ones that have portions of mouse protein in them, tend to be highly reactive, and a lot of people are sensitive to them. So F2-fibatide tends to be preferred between this and Ab6-Mab, because less patients have like an anaphylactic or other allergic reaction to it. It's used for the exact same thing. We use it during the placement of that stent if a patient didn't get an oral antiplatelet inhibitor beforehand. In an ideal world, we would get everybody aspirin and a P2Y12 inhibitor before they have a stent placed, but an ideal world does not always exist. So if they can't for one reason or another, they will get F2-fibatide instead. Again, no real significant adverse effects to know. Just bleeding. And this one also, I want you to recognize that it's available IV because it's that alternative to oral ones. Questions about our adenosine inhibitors or our GP2B3A inhibitors. Everything that we've talked about ultimately is going to inhibit GP2B3A. The question just is, is it doing directly or indirectly? Aspirin is going to do it indirectly because it's going to stop the GQ-coupled protein. Your adenosine and diphosphate inhibitors are doing it indirectly by inhibiting the GQ-coupled protein on that side. These are going to do it directly by directly binding to the GP2B3A receptors. Yeah. The question is, are there anything that we use to prevent heart attacks or strokes? And the answer is five years ago, yes, and now no. We used to, in patients who were high risk for having cardiovascular disease, empirically put them on aspirin. And the thought was, well, since they're at high risk for having a heart attack, we'll put them on aspirin to prevent a heart attack from occurring. Did it do this? Yes, it did. Was that outweighed by the number of major bleed events that occurred, whether GI or hemorrhagic strokes? No, it was not. More people were harmed by giving them aspirin prophylactically than they were helped by giving them aspirin prophylactically. And so what we've decided is that we don't do any primary prophylaxis to prevent these. What we will try to do is to manage their cholesterol really well because we know that cholesterol shearing off the wall is one of the huge reasons that this happens. And that's the cardiovascular risk factor that we want to modify. And Dr. Hum will go through that process and how to modify it. So yes and no. It sounds like a good idea, but in practice, we found out it was really bad. We used to do the same thing for postmenopausal women. We gave them estrogen. We thought, oh, this is going to be really great. We'll increase their bone density. They won't develop osteoporosis. And what we found out was that was absolutely true. But estrogen, like we talked about, stimulates clotting factor production. And so a lot of these women developed strokes because they were put on estrogen therapy. So everything that we do to try to prevent something always comes with this huge caveat of, well, what else is it doing to the body? And so we have to look at, are more people helped or harmed? And what is the likelihood of that? And that's where statistics can come into handy, which you guys will get next semester with Dr. which you guys will get next semester with Dr. Hsu. So there's things called number needed to treat and number needed to harm that we can look at to balance is this likelihood of helping or harming someone greater or less based off of which way we want to go. Excellent question. All right. The last string that we have to talk about before we leave is psilocyzol. There are lots of different drugs that serve as phosphodiesterase inhibitors. The question becomes, is exactly which phosphodiesterase are they doing? And in psilocyzol's case, it's phosphodiesterase 3. You guys have probably heard of phosphodiesterase 5 inhibitors, whether you know it or not. Little blue pills, ******. So that is how it works. It does that by inhibiting the breakdown of cyclic AMP in a very similar manner, just in different cells. It's targeting a different cell. So that does it through PDE 5. This is going to be specific to PDE 3. And so because of that, it is going to prevent and inhibit the process of those cells becoming activated. So it's actually going to stabilize the inactive form of the GP2B3A receptor and prevent it from being exposed in its active conformation. It also will stabilize those secretory granules and prevent them from being released, which causes that feed-forward mechanism. It decreases our acodontic acid levels to prevent that feed-forward mechanism. And because it's going to affect nitric oxide through an indirect mechanism, it ends up promoting smooth muscle relaxation. It makes those vessels slightly bigger. If you have vasodilation, you can handle a larger clot load, right? Think about if I have a tennis ball here. If I'm clamped down on the tennis ball, I'm absolutely going to have symptoms of a heart attack. But if I can cause some vasodilation and be the size of a basketball, blood will just go around that tennis ball that's been created. So that's why vasodilation becomes a really helpful property of this. This does not have an indication for MIs and things, though. Really, the big benefit of this is the smooth muscle relaxation that we see. And so we use this for a completely different indication than we haven't talked about before. We use it for something called intermittent claudication. Anybody know what the word intermittent claudication means? Yeah? Pain with walking. So why is the pain with walking happening? Why does it happen intermittently? In patients with very advanced peripheral vascular disease, you end up getting plaques in your lower extremities and in those veins. The same thing that happens in your heart can happen there and you get diminished blood flow. That diminished blood flow causes ischemia. And so as you're walking, you're not getting enough ATP to activate those muscles and you get muscle pain just like you get chest pain when your heart's not getting enough oxygen. And so we can use this to hopefully dilate those vessels a little bit as well as prevent platelets from sticking down there. And so the goal of this is really to provide some symptomatic relief for patients who have this pain while walking. So if you were to have a patient who's got this pain while walking and they have really bad peripheral vascular disease, this becomes really beneficial. One of the downsides of anything that causes vasodilation is typically twofold. A, it causes the vessels of the brain to often dilate and that causes a really profound headache. So anything that causes vasodilation causes really bad and intense headaches. One of the treatment options that we have for headaches is actually a vasoconstrictor to constrict those blood vessels. So if a drug causes vasodilation, you can almost always assume that headache is one. The other thing that happens when you have vasodilation is you get pooling of the blood in those dilated vessels. And when we're talking about the vessels of the lower extremity, that blood can tend to sort of pool down there. And if you have a patient who has heart failure, struggles to pump blood around their body as it is and is more prone to being fluid overloaded, having this drug that causes vasodilation of the lower extremities becomes very problematic because it can worsen their heart failure. So that's the big thing to know about this particular drug is that it's contraindicated in patients with heart failure. Comparatively, I think the anticoagulants are easier. I think the anticoagulants are a little bit harder. I think the anticoagulants have a lot of, their names kind of make it make sense a little bit. If you know the clotting cascade, you're kind of done. This one, you have to know a lot more of the physiology behind it. So between the two, I think you'll need to spend a little bit more time with this lecture than compared to the one that we did on Monday would be my advice. The other thing about this, I forgot, is that it is available orally. So this is something that patients would take every day to prevent this from happening. So that's the end of Solastizol. What questions can I clarify from either lecture for you guys? Yeah. Your mission for Clope to grow, it's a type of pro-drug. Is there a reason why we don't administer the actin metabolite instead? Is there a reason that we don't administer the actin metabolite instead? So we have another drug in this class that we're not going to talk about. That drug is Prasugrel. But it answers your question. So Prasugrel is active and works to bind irreversibly, very similar to this. It's just very, it's very different. One of the adverse effects of it is it's contraindicated in patients who have had a stroke because it can cause profound bleeding of the brain. And so when we administer things that are active, they also tend to have more significant adverse effects, whereas this kind of allows the body to regulate how much active drug we have at one time. Instead of flooring the system with active drug, it has to get absorbed, go through the liver, get metabolized, and it has a little bit more of a gentler onset. So that would be a reason. I can't say it's the reason. Maybe the active form just isn't stable in terms of us being able to administer. I don't know. But knowing the black box warning for Prasugrel, I would assume that that's another potential thing is when we administer active formulations, sometimes the side effects can be more significant than with the non-activated forms. Other questions about either lecture? At the beginning and end of all of my slides, you guys will see a thing that says, schedule a meeting with me. I can't pull it up real quickly. Please, please, please. If you want to meet to talk about any of this, you can throw something on my calendar. It connects to my calendar right here, schedule office hours. It connects to my calendar. And you can set up a WebEx. You can set up an in-person. If you have several of you that want to come by, I'm more than happy to. And I can also work with Dr. Hum on trying to come to one of the office hours if it just happens to work with what my schedule is for your regular schedule office hours. Other than that, greatly appreciate your guys' time and best of luck on this exam.