Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

that's 74 Wednesday evening at seven o'clock might not be here. The best time to be doing cardiovascular pathophysiology, in fact majority. But who knows? You might have fun in the next hour or so. I'll try and make. This is they're interactive. It's possible. Um, yeah. Um, if you have any questions, please put them in the chat or something and or asked him being this might be a bit longer than an hour. Eso you feel free if you want to get a coffee or something. So obviously we can't cover all of the drugs and all of the conditions. And so that's just a well warning, so I just won't be everything. Um, it's just to really give you guys an overview of what you might cover in in terms of the clinical applications of your one a home, one be bored and one B motor. It's also really useful for any clinical students who are watching, because all of the drugs here are commonly used in clinical practice. Just to keep points before we begin. Cardiovascular pathology is often and really into linked on um, this is a consequence of how the cardiovascular renal system and respiratory system all work on. Do you think this could be This could be really bad in the context of pathology, because often if one system goes all right, the other system or the other systems will follow. But actually, pharmacologically, what we find is that, um, particular drug or specifically, a particular drug class can be really useful for treating a whole bunch of different cardiovascular pathologies. Um, does anyone know a big drug class that we give that can be used to treat a wide range of diseases in the cardiovascular system? I want a neat themselves and say All right. Okay. So, um yes. So, um, like a sin Hypotears or a really important one will come on to those in a bit. But actually, what you find is that a senators are useful for, um, treating a whole bunch of different cardiovascular pathologies. Uh, and really what? What you should try and understand is that if you know how the pharmacy, if you know the pharmacology of a drug, if you know how they work, if you understand the underlying physiology of the normal system and if you understand the pathology, that is how is the system perturbed and disease. You'll be able to, um, use your knowledge, um, to work out what the clinical conditions are. So, for instance, you don't need to memorize that a sentiment is it used for treating X, Y and Z condition as long as you know the underlying process to be able to work it out and then just have a month with this lecture will focus only on the medical side of treatment. For a lot of these conditions on what I mean by that is the drugs that we give to treat these conditions. But as I'm sure you're all over, they're I'm almost every condition it's treatment can be splitting to sort of lifestyle measures on said. This is what we call conservative treatment. So things like stopping smoking or reducing dietary intake of cholesterol, um, our medical off on Kalashnikov therapies. So, for instance, statins or anti platelet runs, cetera and then surgery on this picture on the right is just showing someone. Then stage coronary arterial disease. In this case, they're receiving a bypass graft. So the first case is, um, yep. So I'll read it out. So it's ah, 73 year old woman presents to the GP with a six month history of dull squeezing chest pain. Central chest pain on do you reports that it comes on when she's shopping or gardening, but it disappears within a few minutes after she sits down. Um, she says that it doesn't actually radiate anywhere, So it does. It radiate to her left arm, shoulder, neck or jaw. But she is a bit breathless when these experts happen on in terms of medical history. She's hypercholesterolemia, that is, she has a high blood cholesterol. But apart from that, her medical histories, um, unremarkable. So what do you think is the most likely diagnosis for this woman? What do you think she has put them in the chart? I see someone's put SSRI. Um, I'm not particularly strong on my neuro pharmacology, but I think SSRI was that there's a selective serotonin reuptake. If there's anything in this context, they would be, Yeah, I think I'm pretty much everyone's got it here. It's stable. Angina exactly on this is like this is, um this is so common in clinical practice. So many people have this, um, things to know. First of all, six month history dull, squeezing, chest pain that's, you know, classic angina or chest pain. However, um, I put in this point here. She denies any radiation of the pain to her left arm, shoulder, neck or jaw. Now, you know, in one a fab and you'll you'll know how the the heart is innovated by the T one t five cardiac separate nerves. They overlap with the damage, and and so you get that classic radiation of the pain there and the central processing they also over there. And so hence where you get the radiation to the left side. But in women and also in type two diabetics, um, you could have a typical angina pain. So you have to be really careful in dealing with these patients that dismissed their symptoms that just because she doesn't have radiation of the pain doesn't necessarily mean it's not enjoying them on sometimes that these patients are very few risk factors more being moderately hypercholesterolemia. That might be the only risk factor needed. Okay, so, um, in terms of the underlying pathophysiology, does anyone want to say what? What? What goes wrong? Really? You What's to blame in angina? Yeah, exactly. Plaque formation. Yeah, so? So we'll look at this in a bit more detail, but your plaque formation is this sort of, uh, underlying the main part of energy. So this woman has stable exertionally angina, and this is just a slight detail in its pathophysiology. So on that someone put in the chapel, you effectively have what we call fiber of fatty atheromatosis plots building up in these coronary arteries. Three important thing to remember you, this is this is this takes place over a over many years, many years, many decades on. What it does is Easter progressive stenosis and the eventual occlusion of these vessels. The really important thing to understand is that the arteries supplying the myocardium a woman called functional end arteries that is to stay There is no compensated collateral flow in a physiological setting. This is in contrast, for instance, the gut where you have a lot of collateral flow. Um, the myocardium is unusual in the sense that means that if you have stenosis of an endometry, there will be downstream ischemia. This woman has stable angina, and what that means is that rest You have a certain degree of oxygenated blood slip for coming in. And that's deficient to meet the resting myocardial oxygen demand. Um, if you look to the diagram on the right, I think this might be useful way of thinking about it. So, um, what happens is that you have the coronary artery, even though it's occluded. What you could have is compensating arterial a vasodilator a shin, and so the actual flow that you get to the myocardium it's deficient. But on exertion, what happens is that, um there can be no more dilatation that you're you are already at a maximal dalit a shin on so on exercise when you need that increased amount of oxygen coming into the myocardium, you don't have that on. So you get this scheme era. Remember, ischemia refers to a lack or insufficiency oxygenated blood flow to a tissue. In this case, the myocardium. Um, As a result, anaerobic respiration increases to make up for the A GP deficit that results in increased lactate. Lactate in peripheral muscles is a cause off a crap. And in the heart, this is what we need to angina or chest pain. Is myocardial ischemia, remember? On the other thing is the's patients will have what we call and collaterals developing. These are pathological collectibles. Remember where I said earlier about functional end arteries? In a healthy person, you only have these arteries. But if you have, um, if you have a degree off angina or myocardial ischemia over a long period of time, you actually get pathological collections developing on these develop of it again. Many years, Teo. Many decades. And these write a degree of compensation patients. So can anyone. Uh well, you can put this in the chat. Any pharmacological therapy is we can give to these patients with that to help them symptomatically and also to treat the long term condition. What? What kind of drugs do you think guns for? I think the GT and spray is probably what you're going for. Their Yeah. Gr gr called statins yet really important. Well, else if we go Oh, yes. Um, yes, I weigh. Don't obviously have time to talk about everything I put in red. What? I'm gonna talk about here. Um g n comes under a drug class that we call night. True vasodilator. These are different too. Conventional razor dialect is a little touch on that. Um, Relizen Yes, Dihydrocodein, yet brilliant and run a listen is a very specific drug will look into dihydrocodein. You can have two times. Sorry, and I approve. These are a type of calcium channel blocker on someone said statins. And you know, I'm not going to talk about statins at all in this lecture. But as you know, the most important thing that started to do that they change the ratios and they increase the HDL to LDL ratio. Therefore, they shift the equilibrium of Olympic pressing system into one that removes cholesterol and, ah, deposits from after images. Blacks and they increased the excretion. They're really useful and secondary prevention. That is when someone has already had an episode of myocardial ischemia or they have already had a previous myocardial infarction. Statins could be really useful at preventing recurrence. There also really useful in high risk groups. But I think that's quite well covered in the curriculum. So I'm not gonna fix on statins here. Then we have a few others and beater blockers on. We have it. Aberdeen. You have the case CEOs or the potassium channel opens and aspirin say, um, 90 days a dilators, then well, Nitrazadon eight hours. As we said, GM is an important example. But you can also have isosorbide mononitrate, which is another commonly used one. A little practice on Do these really the mainstay of acute, acutely aborting an angina attacks. So when a patient describes that classic chest pain on, they've been diagnosed with angina nitromethane dial, it is a really good at giving them symptomatic relief there and then so often this can be given as a spray but also has a sub link your tablet. The reason why that's important is if you've done pharmacokinetic. You know the absorption into the stumbling your circulation. It means it's very rapid acting, so offers very rapid pain. Release um, in terms of the mechanism of how it works well, really, you're hijacking the thing. End of the dependent nitric oxide mediated a basic sanitation flattery. So what you're doing here is that GTM nice is already on a nitrate and a monitor it their rule Nitric oxide donuts. Nitric oxide is the most potent physiological activator of soluble handle outside, please. So you have an increased signal is a shin of GTP to see GMP, which of course increases the activity of protein kind is G. You have a phosphorylation of reminds and light chain kind A Z, which inactivates it and therefore it is now no longer able to phosphorylation myosin light chain. You know, decrease in activity is and cross recycling and effectively you have vascular stomach muscle relaxation, which is consistent with arterial of a Xyzal vacation for one, a medic and one B medics, please revise that partly that that protein kind is mediated phosphorylation and in activation of my side like Jane Kind is, um if you get a nest egg question, uh, you just write that diagram out, it's yeah, like, it's a good bit of detail, which I guess they made you mentioned in lectures. But, um, it shows you understand the subject, I guess, um but I think that would be useful one for you guys to learn. Um, in terms of the interesting point here is well, these night, Trunzo diet is what they appear to do. So they actually cause preferential razor dilatation of the coronary collaterals that I talked about earlier. Um, this is in contrast to say, dipyridamole, which is a very general razor dilate. And the reason this is important is because if you would generally amazing dialect, the coronary circulation, you actually divert blood flow away from the stomach parts. And that's called a coronary steel. And that's really bad, because already the ischemic part of being under perfused So if you preferentially amazing, I like the collaterals, your shunting blood from those areas that don't need as much oxygenated blood and you shan't it to these less perfused. It's Stephen parts say, uh, it works really effectively. The other thing is that the vasodilator central Maine to central venous pressure decreases the preloaded increases and the my cardio work decreases in terms of how this actually treats stable angina. Well, as I said by raise a dietician only does it beep. It's preloaded cetera just increases the perfusion of oxygenated blood to the myocardium. And so you have a very rapid relief of the angina or chest pain. Okay, so the other class of drugs are beach blockers. Now, on do this sort of the next hour or so, I'm going to talk about a bunch of different drugs, But remember what I said it to start. All of these drugs can be used for many many different cardiovascular pathologies and beater blockers are a mainstay of cardiovascular treatment. So we'll talk about that mechanism here. And also you mentioned them later on for the other cases that we have. Um, first of all, um, again from one a medics and one b medics on meds. If you're here, you need to know your adrenoceptor. So, um no your adrenoceptor. So the ones you should know about the alpha one, which are GQ coupled, Remember Gi alpha que stimulates foster. I m a C beater which Cleaves pit too into 93. And Dag, the I pee three will have generalized I'm p three receptors in the soccer and a plasmid particular membranes. And it will trigger a calcium release. Calcium releases disproved muscle contraction. And so often on agonists of alpha one receptors so nor adrenalin in the body. They will, they will cause vasoconstriction Dag, remember is also a a product of pick to licensed dying will activate protein. Kind of seem to have its own effects outfit to adrenoceptor RG I couple remember and g I will that inhibits, uh, cycle is and the increase is the liquid pressure. CMP beater one beat it to and beat a three adrenoceptor zar all gs couple. So they stimulate a dental outside, please. On they increased the interest of concentration of cyclic GMP. So be two blockers. What do they do? Well, cruising the name they antagonist the beat Adrenoceptor is the first one we developed was propranolol on different along is nonselective So that's a that was that was great for, you know, reducing heart rate for instance by antagonism be 21 adrenoceptor in the sinoatrial node. The problem is we have beat it. Two adrenoceptor is in the bronchial smooth muscle have the mucus glands. If you antagonized those, you're going to get bronchial smooth muscle contraction and increased mucus production things you don't want in a patient who has diagnosed established COPD and asthma and so propranolol. And in fact, all beater blockers are actually contract indicated in patients with asthma and COPD. Then we have other drugs like atenolol. Oh buys opera long carvedilol and below atenolol and buys operable are what we call cardio selective beat adrenoceptor dryness to stay. They are pretty much selected antagonists or GS couple beat a one adrenoceptor on goes of the two that we used in clinical practice. Commonly, carvedilol and the devil have additional actions. So does anyone know what car made a load us in addition to be 21 antagonism. Yes, yes. So how foreign antagonism is really important? Yeah. So carvedilol is an hour for one antagonistic. Well, and as I said earlier, remember G two couples Alpha one adrenoceptor was vasoconstriction send you on antagonize the night. We're going to be reducing the after load on so you'll reduce the work. The heart has passed the resistance against which the heart has to pump. Now carpet holds also cardio protective. Uh, because it's it's anti inflammatories, anti inflammatory and antioxidant effects number below is a beater three and a nystatin. Well, for some reason, agonist, um, of GS couple of beach or three adrenoceptor in the myocardium is associated with 90 bucks. I'm production a 90 bucks. I production because it stimulates under the your nitric oxide seven days. And remember what we said. The nitric oxide is a potent basal dilator by the pathway we talked about earlier. And if you've azo dilate, what's going to happen is, um, you're going to increase the blood flow to the, uh, coronary basket trip Teo beat of lockers as a whole. The the way, the way in which they work is simply they reduce the catecholamine addict out flow to the cardiovascular system to really understand how they work on it. It's important to understand what beater one adrenoceptor again is, um, normally does. So, um, nor adrenaline and adrenaline are the endogenous agonists off beater one adrenoceptor on. As I said earlier, remember, it's a G s couple receptor, so dental last. I guess it stimulated. You increased the interest on your levels of CABG on on. This has a huge number of effects across all body tissues. But I want to really concentrate on things that relate to the cardiovascular system on. I'll get what I'm weakest on out of the way with first in the brain and increases sympathetic outflow. Please don't ask me how that happens. I'm I'm sure people will offer a much better answer. Eso That's consistent again with increasing the sympathetic out pretty hard on the heart itself. When it does well, it increases the chronotherapy. That means the heart rate increases. Um, the reason why it does this is because increased CMP Cycling A M P is an agonist of the hate C N channels. And if you what happens is you get an increased in the activation of hate C N channels on you shift their activation, um, at home or depolarizing attention. And so the funny current increases that increase the heart rate. You also increase the activity of peek A, which phosphorus calcium channels. And so things like the Inwood tee time and l type calcium currents increased Another big thing. It increases the actual force of myocardial contractions. So why in a true pee again, it's to do with PKU phosphorylase it the, uh L time voltage gated calcium channels and yet increased calcium influx into the myocardium. But remember, from your one a home theater in terms of muscle contraction in cardiac muscle, it's an open calcium economy, which means that you're not gonna get things coming game. But you also get released from the M released from the cycle plasmid particular man again PK will phosphorylase it and sensitize ranitidine receptors. And so you get more calcium release. So again, more calcium in the cardinals, so more powerful contraction. But I think that people always forget is that not only does it increase heart rate, increase my card, you're contractivity. It also increases the rate at which the myocardium relaxes because to increase heart rate on, contract it immediately. You also want to make sure that it relaxes and gets back to its resting point more quickly. And we call that increased new security. The way in which it does this is that if you increase the activity of DKA you force for a late possible amber on, that decreases its phosphorylation of circus. So ultimately, what you end up doing is you end up, uh, recent westerain the calcium back into the socket plasmid particular at a faster rate. You also have phosphorylation of potassium channels. And so the report arising potassium current, which are responsible for the down stroke. On the my sight action potential, they have been faster. And so you affect you to get a terminal reforestation happening faster. That's on the heart. On the other really important thing is and the kidneys they beat blockers are also good in people with cardio renal pathology. Because the just a glomerulus cells of the Afrin tarty really have these, uh, these gs couple beach one adrenoceptor. And what do these just a glomerulus cells of the Afrin dot here. Real release. Does anyone know? Yeah. Read and perfect. Um, the renin angiotensin out of steering system is is extremely important. And if you're doing one a home, I would advise you to learn that one. It's really important. It's also really useful to get your head around for one am sorry. One be motor on any clinical medics watching, you know, that that system is dysfunctional in a lot of, uh, cardiac pathology and suddenly in heart failure, patients with heart failure have disregulation of this system. Um, you What you're doing here is, in a way, that beetle blockers, they reduce the amount of reading that gets released on, by extension, that reduce the amount of angiotensinogens that gets cleaved 100 10. So one, and subsequently you reduce the activity of the system. Overall, what is all of this doing well on your reducing? Um, well, that's what meter blockers do. Sorry. Overall, what is nora grand dreaded in doing? What they do is they increase your cardiac alper, they increase the blood volume. So you have increased preload. They also increased the answer of leprosy Increase after load. Chronic beetle one adrenoceptor agon is, um, is associated with increased work on the heart. And actually, some studies have shown the long term, if you keep on, are stimulating. Beetle one adrenoceptor is as happens in chronic heart failure. You actually get a down regulation of the receptor, and almost this leads into a vicious cycle because the heart is already trying to stimulate beach one receptors more. If you get receptor down regulation, that process goes into overdrive and you actually increased cardiomyocyte a pop Tosis on. And so this makes a lot of sense, right, because if you antagonist these receptors using beach blockers, you're treating these. You're treating all of the adverse consequences that come as a result. Now, how does how to be two blockers treat stable angina? That was what I patient had. Well, they really work by four main ways. First of all, you're decreasing Cronin trip, he said. You decrease heart rate, and so you increase the proportion of the cardiac cycle spent in diastole. It's really important to remember the Unlike peripheral tissues, the heart is perfused in diastole. That's because when the heart is contracting, the muscles will compress the sub endocardial fusing vessels and so you can actually get confusion of oxygenated blood in Systole. Instead, it's in diastole. If you decrease operate and you increase the time spent in diastole more oxygen into blood to the myocardium. You leave it on my card in the scheme here and if we need treatment, stable angina, what else is happening with increasing on a trip? And if you decrease an attributing, you're decreasing the amount of oxygen that the heart needs to work. So again you're alleviate the demand to supply the heart with oxygen. And then finally these two points you're decreasing. One morning, it's increasing BP and they decreased preload and after the respectively and again you're decreasing the amount of work that the heart has to do. And by extension you're decreasing the oxygen demand. So the two blockers are really useful for treating stable angina. And in fact, nitrobenzene dilators that bought an attack on beater blockers are really important. The other big class of drugs are calcium channel blockers. Now again, calcium channel blockers are one of these drugs that we can give to treat a whole host of different cardiovascular pathologies. Can anyone think of some pathologies other than angina that they might be useful for without looking at the diagram on the bottom right of the screen? Actually, you know what? All three of the ones that I was thinking of around that and it it's angina, hypertension and a with me. Um uh, So they're released for for treating on these air in class of drug, you very commonly prescribed a clinical practice. And you should be familiar with these drugs on, Certainly their mechanism of action, how they work. Calcium channel blockers are a and quite a nebulous class of drugs. And we didn't really split them clinically into so called dihydrofolate in the nondihydropyridine the diet B m sort of quintessential die 100 period in his knife. Better be. It was felt to be in a new clinical practice. Because when you use, um, lot of teen, um, in terms of non died a pretty and you have the female kinda me and such is Barabbas. Millions of benzodiazepine such as diltiazem not to be confused with benzodiazepine. Okay, but you're completely different class of drugs. See, what do these do? Well, they won't. Calcium channels. Um, they're not l type calcium channel, but it's really important to understand this distinction between dihydrocodein or D H. P's on nondihydropyridine dihydrofolate in calcium calcium channel blockers on interact with a particular region off the, uh, off the anti voltage gated calcium channel on. But they do is they actually preferentially block voltage gated calcium channel that I really inactivated stick. And so what happens is that they tend to block those ones in the smooth muscle. This is because remember the resting. Well, does anyone know what roughly the resting action. But there were sorry. The resting potential of a typical ventricular cardiomyocyte is Yeah, mine is 82 minor. Yeah, exactly. Minus 90 million bucks. I think. I think that's what we've got taught as well. Yeah, on anyone has it against us. To what their resting potential for, uh um a, uh, vascular smooth muscle cell is yeah, minus 40. Might be a bit on the high side, but certainly minus 52 minus 60. Yeah, exactly. Minus 52. Minus 16 Millibars is the figure that comes to mind, but yeah, the point is it's more deep water I said, Remember the calcium channel? He's evolutionary related to the sodium channel. Say, if it's depolarizing slightly depolarizing, what you're gonna have is a higher proportioning inactivated state. So when you give a patient nice, very keen on a lot of beans or a lot of teams, then preferentially going to bind to you and so block these inactivated channels in the peripheral stomach muscle. And so how is that going to work to treat stable angina? Well, your clue. You're going to cause peripheral arterial a vasodilator a shin. You'll take a peripheral. Resistance decreases arterial BP decreases the afternoon decreases, and that's how they reduce my card sharks in in your mind. We can contrast this with the nondihydropyridine such as verapamil and diltiazem. They will target different regions again on the same day. Maintain for them. Talk also Target domain four of the Voltage Gated Council and they preferentially time with those are rapidly opening and closing voltage gated calcium chapels on day. Where do we have rapidly opening and closing bolts of educated calcium channels where we have that in the ventricular myocardium? Because of the fact that the ventricular myocardium on resting potential is about minus 90 votes. You're not going to have them in an inactivated state. They're going to be inactivated state, ready to rapidly open and clippers. And so you will block them and say What you then have is, um, First of all, if you block those ones, you're going to produce calcium influx. We're going to reduce the heart rate, and so again, you increase the proportion of the cardiac cycle spent in diastole and you increase blood flow to the myocardium. You also decrease the amount of calcium that straight of enters. Because remember, on muscle contraction cardio, cardio my sight is an open calcium economy. Calcium editors from the extra special A space. You decreased my card. You contracted the results, and over time this adds up. Do you get a decrease in my cardio oxygen Depart so you can see my understanding the mechanism of action. You can understand why this would treat angina, but also I go back to the previous life. We said it treats angina very reducing preload, and afterwards, But if you have reduced afterward specifically, you reduce joints operate for resistance. You also will treat hypertension. You also treat the arrhythmias some hair with meals of the day, then or used not much for, uh, the campus. I think someone mentioned Ranolazine earlier. So, uh, Hope Runner lysine is it inhibits this really unusual kind is the Inwood sodium current that specifically, it's not the early in with sodium current that contributes to the fast upstroke of the myocardial action potential. It's the late, inward sodium current, Um, and what happens is that if you inhibit this late in word sodium current or late in a, what you have is a decrease in the end amount of interesting. The sodium you end up with you get an increase in the inwardly directed. It's sodium electric, comical Grady in. And so you have increased the activity of the sodium calcium exchanger. If you increase activity of the sodium calcium exchanger, Mork calcium is going to be extruded. And remember, calcium contributes to muscle contraction. So what happens is that the ventricles sort of contracting as much. It actually relax. This is especially at the end of diastole. You get reduced wall stiffness on. The reason this works is because you get less compression of those some endocardial vessels, so you actually increase the perfusion of oxygenated blood to the myocardium Minimal eczema is actually, you know, in the grand scheme of things is a relatively new drug, so it's not as common in use for angina, but, you know, in principle, it, um it works on clinical trials have shown that it does work on increasing the USC around her dizzy, be prescribed as well. And finally, of Aberdeen. This is this is a really good, um, good agent for reducing the harboring. And the way in which it works is because the hates the end channel that, um, the channels that was responsible for the funny on it inhibits thumb. So if you get decreased conductions of the funny currently, decrease the heart rate. And remember, the reason that works that negative current therapy is because you increase the proportion of the cardiac cycle in diastole. And so you get an increase of the perfusion of oxygenated blood to the myocardium. Have a look at panels. See here, um, that you can see what it's doing, it decrease the heart rate, and that's how it house to treat angina. Now, here are a few drinks we didn't really talk about here on Potassium Channel open. It's on our major class of broke on aspirin and statin, I think I said statins. They used a secondary prevention early. And I'm not really into talk about statins much more. I'll get onto aspirin in a bit. And again. Aspirin is really used to prevent the complications of angina or downstream effects of China. Kidney plus channel open as well. Does anyone any? Does anyone have any examples of potassium channel weakness? I mean oxygen? Yeah. Minoxidil. Brilliant. You also have Nicorette. Go on. Does anyone have a work? Apart from the fact that the open potassium channels, you say I like to think of them as pretty much working in a similar way to calcium channel blockers. Calcium is needed for muscle contraction. Um, potassium, remember? And the flux of potassium is a hyper polarizing current. Okay, So came for capers. Channel opens. What they do is they They opened, uh, potassium channels on. So you get an increase of the conductor to be hyper polarizing. Get a hyper pressurization of vascular smooth muscle, it relaxes, and if it relaxes, you get decreased in peripheral arterial a vasoconstriction. The total brutal resistance drops you're reducing after load. You reduce by pressure on the context of angina, you're reducing the resistance that the heart has to pump against, incidentally, displays of dilation. Basics. This is one of the reasons when minoxidil actually works so and minoxidil is given as a spray, for it's touted as a treatment for boldness. So if someone has a bowl patch, you can go to Boots on by. Think it's called Re Game and Regain is minoxidil. And what what that does is especially dilating the arterials that supply the hair follicles and more nutrients go. It's it's supposedly supposed to make your hair grow back on. If you have a bold spot and Nick around, Oh, actually has other effects, which we really just realizing. So nick around or has cardio protective effect. Not only does it stimulate the opening of those potassium channels, I talked about early and actually stimulates the opening of a to be sensitive potassium channel on them. Um, I took Andrea, and that's been associated with reducing the rate of 80 p depletion in acute episodes of giant ischemia. And so you're reducing the transfer that progressing to a full blown infection a nickel and A is also a 90 dockside donor. And remember what we talked about earlier? Nitric oxide dependent baser. Relax. A shin on. That's quite okay. Um, right. Case number two. 65 year old male. He comes to any with four hour history, this time of Central crushing chest pain that importantly, is failing to respond to his reliever 90 razor dilator spray. So it's taking Degen's not worked. He's also nauseous. He's vomited a few times, is sweating profusely, and he's got discomfort in his neck and jaw. You got pain. Also down his right arm is well, you know, from his medical records. That has been a lifelong smoker. He's got a history of, um someone said It's Rogaine. I'm not sure I was. That was read up enough. Um uh, yeah, he's a lifelong smoker. He's got a past medical history of diabetes type two diabetes, hypertension, uh, kind of cholesterol in your someone put in the chat. What? This diagnosis is this is, like, textbook like textbook case. Yeah, heart attack here. Am I? Yeah. Um, does anyone know the different types of quit heart attack Acute coronary syndrome yet? Does anyone know what the different types of acute coronary syndrome up. They're three different types. Yep. Same intense. Tell me the two things. The up. Yeah. Unstable angina, Yes. So unstable angina. Is this really am We talked earlier about that woman in case number one. She had stable angina. That is to say, it relieves with rest. Unstable. Angina is something that doesn't alleviate with rest on. D also doesn't respond to GT and spread Stemi and Aniston your district from angina. Because angina remember is myocardial ischemia. Stemi is infection and also an instant noodles in function on. Then we'll get to the end of it what that means. So really and any any Well, for everyone, watching this regard is a very a preclinical or clinical. We need to have a few investigate investigations at the top of our mind because what we want to do is we want to make sure that if this isn't am I pick it up on, But look at the underlying, have their physiology answer pharmacological treatments we can use. So my departure. What do we do? Well, the first when I was someone comes into any with suspected m I. We want to have a look at their basic labs. We'll do that for everyone, right? So you want to have a look at How do they look generally at a sweaty and clammy and anxious? I can't remember the name of the signs, but often will Patients will do is that when they have this crushing angina that doesn't respond, they'll make a fist. Put it over there chest that we really anxious, all sweaty. And that's a sign of the sign that this is actually something a bit more serious, that angina. You also want to make sure you take it. You have that pulse. It could be tachycardia, that BP, their respiratory rate they'll be talking. Make that is they'll have a respiratory rate greater than 20 breaths per minute on you will have a look at their oxygen saturation. These are things that contribute to your A B, C. D. E. Assessment. Cool when it's when we were. When you've done that, we want to weigh, want to do things that are easy. So first of all, we want to do a D c g e c g really quick, really easy to do. I'm on. If you have a look? I think it's the diagram on the bottom. Yeah, there's a diagram here. It shows you the CD changes now, Um, acute coronary syndrome. Mr. Mom mentioned that she has three different types. You can have a stable angina know as a instead of people stemi now in unstable angina and end steady the class. One of the findings will get is a T wave inversion on T wave inversion is a sign of myocardial ischemia. Um, on if you find that you should be worried. Other thing is ST Depression again associated with, uh, ischemia. Some worrying Sign Teo, you have probably done the CDs in one a home. And you know, the basic components of the CD the P Wave QRS complex, The ST segment that the T Wave this ST segment is really important to look up. The sort of really, really worrying thing is if that ST segment look at look at what's normal on the EKG. The ST segment should be high, so electric. If that ST segment is raised for the whole leg, we hold out a tombstone. ST Elevation. It's tombstone because it looks like a tombstone, and it's also Tombstone, because this is really bad at the patient. Might die from it. We hold on ST Elevation myocardial infarction or a stemi. They are associated with severe blocks, severe inclusion of main coronary arteries. And today are things must be treated. And the gold standard for their treatment now is percutaneously coronary. And eventually, um, you take them to a regional center like pop work on you. Um, when you stack them, what else can you do? What you can do? Blood test and other blood tests? Um, you have to be careful because, um, what you looking for? A cardiac bio, Marcus. But you have many different cardio. And no, all of them really rises quickly. If somebody's having a stemi, the STD will pick that up instantly. If someone is having if someone's having a heart attack and wait for the Bloods, you have to wait at least eight hours for some of these reports of wants to go up on. You have to do serial blood tests because in elderly patients with poor renal function, they won't be excreting these in their urine as much. And so they're going to have them elevated anyway, So What you need is a baseline assessment. And then you want to do serial measurements to make sure that actually, this some this person is having an acute elevation of these cardiac biomarkers. Does anyone know which ones we look for? Yeah, I think Martin is covered in quite a quite a comprehensive comment. They're actually, yes. So that's that's management of unsteady, I think. Um, yes. So, uh, proponents of the troponin of the classic one Do you know which proponents think this was mentioned in one a home. You have. You have many different components. But troponin, I proponent tea. Yeah. Yeah. You haven't. You have a few of those. I am t a commonly used in clinical practice. And, you know, again, you have to be careful because the elevation is after the eight hour point. You also have creating kind of m B, which is a cardiac isofl, um, on really blood tests of the way which we differentiate between unstable angina and stemi. Remember what I said about stable angina? It's still myocardial ischemia. When it's a ski me A. The myocardium is still technically not damaged. If you have damage to the myocardium cell death has happened on where so deaths happens. You have rupture of the plasma memory. You have interesting contentedly picking out. And it's only when those interesting look wanted to be Count. You get an elevation of these cards. Um, remember, if they are elevated over, damage to the myocardium has occurred. Um, so, for instance, you see a patient that we see GI has t wave inversion of ST Depression, but it doesn't have ST Elevation. They have the history consistent with with some type of acute coronary syndrome on their proponents a CK and be around. They have an end steady. Okay, that's how you were diagnosed, that the other thing you look for you could do is imaging on their four imaging studies that we could do chest X ray just because it's really easy. It's It's really quick with doing it for 100 years. What can you look for? Well, in a heart attack, it might not be the most sensitive one, but for a patient with heart failure, they'll show enlargement of the heart beat black hardy and regularly. You could also check that thing, right? Pulmonary edema, which will come on two later You could also do what's called a CT. See a. That's a That's a CT coronary angiogram. And what that's doing is checking the patency of the vessels. It's basically an angio angiogram. Um, I think in the one a farm applied anatomy sessions that come in. I have mentioned this contract to see which are trees are included. A cardiogram is increasingly popular for the assessment of, uh, pathology and cardiac MRI. Historically, cardiac MRI was quite difficult to do because of the movement artifact. You have to get our cardiac movement. But now, with with the fact that it's become cheaper and also many more people trained in it, it's it's increasingly being used on a cardiac MRI is really becoming the gold standard for many cardiovascular pathologies. Uh, here's an important point. What did these different I words mean? So you have things like this scheme, you an infarction. Now it's Kenya is really important. Understand? Ischemia is a restriction in the supply of oxygenated blood flow into a tissue. Okay, that's what ischemia is gonna have my own cardio ischemia, which means it's to the heart, cerebral ischemia to them, to the brain, and a referral is skim, unisex leg muscles or whatever. Infarction is thrown around a lot, but in function specifically is cell death or necrosis due to ski Mia, that is. What in function is so myocardial infraction are your heart attack specifically means, and the crisis has a card. Second read to myocardial ischemia. That is the definition of a myocardial infarction. It's also really useful to have in your head why this would happen. And for me, I'll actually get in three ways. It can happen for three main reasons. First of all, you have another relative spark. It is growing and growing and growing, and eventually it grows to such a high point that it's straight up stir noses or includes that coronary artery and you don't get that. Now that's super red because it's very red and just have a blockage like that. Number two and number three have far more common. What happens is on often in the context of other co morbidity. So you have hypertension or, if this is just a block, these unstable, the top ruptures, and now you haven't exposed surface that activates the coagulation cascading. You have thrombosis happening from versus on that forms of thrombus that cleans blood flow to that statement. The other thing that can happen is that actually, when it ruptures, the park ruptures. Plant fragments is a usually liquid or cholesterol masses. They should go off somewhere else. The these are called embolize, or you can have a throb big breaking off on a strong Ms forming elsewhere. These are called thrombo embolic, and again I could need to stenosis or occlusion of a distal artery. It's really useful understanding the difference between thrombus and embolus. I don't think it's made it clear in the pre clinical course or in the clinical trials, for that matter. I think I have these definitions in your head. So Throng Best is a mass that is formed from constituents of the blood within, indeed, circulatory system during life. So that's the wrong business. Typically, composer things like your firebrand plate leads and track every three sites, and leukocytes, an embolus is is quite distinct. Ambulance is any intravascular mass that is carried by blood flow from some point of origin, say, Excite A impacts a distant site. Six. I'd be, um, the source of in Hamburg. It's can be many different things. You could have a rambling if you accidentally introduce a gas into the circulatory system. If I am not a fluid enters the circulation when a woman is giving, it could lead an amniotic fluid ambulance if bone marrow. If you have a fracture of a Longbourn. Staying fracture. Femur. Bone marrow from the middle of the femur enters the circulation system. You could have a bone marrow ambulance if a plaque ruptures, you could have a fat or cholesterol embolus all. If you have a thrombolysis and gets formed elsewhere, you can have a strong wrote embolus. And, really, it's number two and number three it out of the cause of most pathology on this is very similar to what happened in stroke as well, except instead of a coronary artery, your including some cerebral tissue perfusing artery again. So if you have this concept in your mind, you'll be able to, um, make a really compelling argument when you come to write your essays. So one of the pharmacological treatments, um, well, the pharmacological treatments. This is for a myocardial infarction. As I said earlier, the gold standard for the gold standard is changing now. We just you know, if someone has, if someone has a dime in France, tell me and they present with it two hours eso within 12 hours, a symptom onset, and you could get them to a on potatoes corn reintervention center. Within two hours, you will just ship them off. Their on day will stand the coronary artery. However, pharmacological therapy still remains really important because you're still have to wait two hours to get your stent done on. If you haven't. If you have any systemic, you're still relying on the's different trucks. So the two major class of drugs will talk about the anti platelets on the anticoagulants. It's really easy to get them confused, but they distinct classes of drugs, and they do different things. There are also other treatments that we can give, which I'll talk about the very end. So aspirin Aspirin is a derivative of aminosalicylic. It's salicylic acid. We've known about aspirin as an agent since the time of the ancient Egyptians, but aspirin is really, really important in the acute pharmacological management of my consulate function. When a patient comes with instant me or stemi, what do you do? You give them a 300 mg start dose of aspirin And why Why is this important? It just what this Does it really mean? It's how much damage can occur. How does aspirin work? Well, aspirin is, um, an irreversible inhibitor of Cox Cyclooxygenase. Specifically, Cyclooxygenase is one acetylated have. No, it's a available fortification of Syrian 530 in the active site. And what it does is it basically inhibits this in both platelets on the vascular under dear. Now, platelets are Well, that's that's a chat off platelets. Do platelets have a nuclear sort of do not have a nucleus on the nuclear or a nuclear? A new Kate in perfect. What about vascular endothelial cells? Nuclear did. Exactly. So you have this dichotomy here. You have this a nuclear platelets on nuclear. It'd end of the year. And in platelet, if you inhibit Cox, that's it. The platelet, maybe over sensitized more cops on before any cyclooxygenase prostate gland into a prostaglandin derivative. I'm specifically this with me thromboxane eight years, um, which is a derivative of a record on a cast. It you're not going to be able to produce an animal. So DXA tuned. Corruption increases. Um DXA two is basically constrictor. It promotes platelet aggregation, and it's a pro hemostatic agent. It constricts blood vessels. It stops bleeding beating, but it's a potent agent informing the clot. Conversely, the vascular endothelium. If you inhibit Cox because it's got a nucleus, it can just synthesize walk ox. Okay, transcriptions, upregulated transfer translations. Upregulated eccentric. A record chronic acid derivative in the vascular endothelium, for instance, Prostacyclin or PG I to will continue to occur. Trusting prostacyclin or PG I do is a laser dilator, and it inhibits aggregation. So if you give someone aspirin, certainly a high dose of aspirin, you're shifting this equilibrium towards the muscular endothelium and away from the platelets. And that's consistent with, um, inhibiting him a Stasis. And so if you reduce the risk of informing and very big strong muscle from ER, you also shift the balance towards vasodilation. And remember what we said earlier. Visit annotation. Increase the perfusion of oxygenated blood to the myocardium. So really, aspirin is helping to keep your heart viable or as much of the cardiac tissue as viable. It's possible on top of aspirin. We also get what we call P. T. Y. 12 receptor antagonists. Now, um, add any nuclear times have a whole host of receptors you have, Pete, you exercise and be two yr is you also have a different types of the dentist in receptor of the A one a two a hb a three Be too wide. 12 receptors are antagonize. Sorry. The speedway 12 receptor antagonists are offered given with aspirin in a patient who has a likely unstable angina or myocardial infarction. Three main drugs here, pretty girl presents grow into cancer along. And how did they work? Well, they just inhibit the lining of 80 ADP. Sorry to these pizza. A 12 receptors on a D. P is really important getting platelets to stick together. So again you're reducing the risk of thrombosis of thromboembolism that clamp it growl is it's sort of like it's been the mainstay of treatment, but increasingly rare using to Cabral on, Does anyone know why? That is why we're using to card little more often. I'm part from the fact that it is more effective. Why? Why would it be more effective? No. Okay, So, uh, you probably will have done this year in I don't If you do this in one A. But you probably do this in one be motor. Pharmacokinetics liver has this endogenous seen a biologic metabolizing system on a major class of enzyme. To do this with the cytochrome cytochrome. So you have a kid to see one line sunscreen people 50 enzyme, so you keep to see one night. Now the metabolism of apparently well relies on that. But some patients in the general population just don't have functioning. Copies of kicked you See 19. And so what that means is that the metabolism is really compromised to Cabral doesn't need to be metabolizing that it's not approved for Dr Break. It just works. And so what happens is in a on average, more people to Carol works better because it doesn't have to rely on this mechanism. Having said that in anticoagulated patients that these patients were on and subset of antique, a regulation already is because of some propensity. Just thrombosed Computer girl is favorite because you want to reduce that risk. Now we get also a class of drugs that you're less commonly used, but still these. These can be given in conjunction with aspirin and Peter, 12 receptor antagonist These are the Glyco breaking to a and very black writing to be and three receptor antagonists. So you have to sort of small molecular agents, activity outside and terrified. Too rough about on. Do you have a monoclonal antibody? Have 16. They work by on antagonizing or inhibiting that like a protein to be and three receptors. But abciximab also inhibits of introduction receptors on. Ultimately, what they're doing is they're reducing the amount of fiber in it and the bridges together, and they also reduce platelet aggregation. And again, this is reducing the risk of from racist of problem. But it's a I thought would be good to talk about the curricula in Cascade here because on well, this looks really complicated And yes, when you first look at it, it is really complicated. But I think it's really useful. Don't have, like, some idea of this. So what you've got, you've got two pathways really leading into it. You have the intrinsic part way on. That's really started off by some exposed surface, usually services that negatively charged. And so that starts up with 12. So you go from 12 to 11 above 11 and ultimately culminated 10th, then you also have this extrinsic pathways. If you have troland to a blood vessel, so ask your injury. You start off with factor seven and again accommodative back to 10. And then you get to his common, partly downstream affected end, whether you have a factor 10 and finally complex, which converts to to to a and then two a finally let's fibrinogen to fiber. So this part of the reason why it's important to sort of have some understanding of this part is it the anticoagulants drugs know the anti platelet present? We've already talked about the anti caregiver drugs work by inhibiting some component off this part. Okay, say what we have here in terms of the major anticoagulants of the context of our patients. Um, what we want to do is we want to reduce the risk of a secondary strong about it event. We want to reduce the risk of that happening on the two sort of major drugs that we could get. Well, we could give them fund a paradox. Um, which binds the anti from the three and what that does is it accelerates. It's inhibition of downstream factors in this case, a factor. 10, 8. Um, on. Um, we could also give low molecular weight heparin. So, for instance, it out apartment low. Molecular. What happens is related to heparin, but they have a better pharmacokinetic profile and increasing the US Seeing these low molecular weight heparin is being used. Ultimately, what this is going to do is if you follow this path way down here, Well, um, you're going to reduce the conversion of factor to two a. Then you're going to reduce the amount of fiber in it and it gets converted to fiber in. And ultimately you're reducing the amount of the risk of a major thrombus forms. People ask What's the difference really between these two agents? Well, um, because they both sort of acting a very, very similar way. The difference is that the difference is that, like your low molecular weight, heparin's also inhibit. If you look here, there are also inhibit thrombin, whereas the funding parents only inhibits today. And the reason for that is that they both will grant from the three what When fondaparinux binds Dante thrombin three. The confirmation of change that it elicits is slightly different. And so the relative the things that it inhibits are slightly different, that that's very, very neat point and the other pharmacological treatments are as we've got here. So morphine. You probably know that morphine is an opioid, and morphine is used for pain. But actually, studies have shown recently that you shouldn't really give patients who are having a myocardial infarction morphine unless they're in severe pain because associated with worse outcomes oxygen again. You know, if you're if there are estrogen, saturation is falling below 95%. You give them oxygen. As we said on Nitro basal Dilators, we said earlier how they work. And again, it's really easy to see, having understood the mechanism of drug action, why they work in this context. They're reducing the after load. They're reducing thing about of force of the heart has to pump against that, too. In a strange heart, you're reducing the work it has to do. These have lockers. We talked about how they reduced creditors would be. I know tricky and all the good things that happen at the results of that and statins when someone's had a heart attack. If it was a new heart attack on, but they never had a previous cardiac event. Before you started on statins, you reduce the risk of having a future heart attacks. The final big case that will do for today is this is the 76 year old woman who comes to her GP with a three month history of leg swelling bilaterally, progressively decreasing. Um, uh, exercise tolerance on increasing fatigue. You examine her and you find that she has a low BP, but, um, high central venous pressure so that that could be seen on the neck has a raised jugular venous pressure. So the veins are really prominent on. You know that two years ago she had a myocardial infarction, which was enhanced stemi. And so it was managed. Pharmacologic be. What do you think this woman has? What would you diagnose this woman? Because they won't have a study that doesn't have any suggestions. Tarpinian. Brilliant. Now, heart failure is, um, interestingly, hopefully is not a diagnosis by itself, but obviously it's clinical vignettes describes heart failure. But the key thing is, um, we never say that someone has half in and leave it at that. Um, heart failure is always caused by some. Think if that makes sense. And specifically, this woman has heart failure caused by her heart to have my ideal infection. So the specific diagnosis for this patient is a bit of a mouthful, but it's chronic, are failures of chronic because it's been happening over a a few months rather than over a few days. Not cute on, say, she has a reduced left ventricular ejection fraction. That makes sense. Because, remember, she said she was being retired. Left ventricle pumps into the aorta. The systemic circulation. You're getting less volume into, the less cardiac output. If you get less kind of habit, your perfusion of oxygenated blood decreases, and this is all due to the full thickness. Anterior am I that she's that before. So heart failure. Uh, I think there was a stone was like opinion piece return a few years ago, Um on there was in as like, 1000 cardiologists and cardiac researches about a definition failure. No one could agree on the definition for heart failure because it's actually so so difficult to define, but a useful way of thinking about it. It's not a true definition, but it's a clinical syndrome. It's a combination of symptoms and science that a secondary teo, a decreased ability of the heart Teo pump sufficient blood out to meet the oxygen demands of her for tissues on. Remember, it's not a final diagnosis. It's always caused by some pathology with the cardiac structural function on. Increasingly, we're seeing that there are two types of heart failure. And really, you could split them into heart failure with reduced ejection fraction and heart failure with preserved ejection fraction to heart failure with reduced ejection fracture. And I like to think of the heart as a sort of floppy bag. What you have is this. You have these really flashing ventricles and filling off with probably an increased amount of blood, but they're just not able to generate as much pressure. And so the amount of volume that the pump is actually reduced. So this is a systolic dysfunction. It's problem with men. Trichuris Systole. On the other hand, you have heart failure with preserved ejection fraction. This isn't a stiff bag anymore. This is like this is This is like a thick, stiff heart, and what happens is that you're reducing the amount of blood that you feel, But the heart is still able to pump our on normal, sometimes Morgan normal amounts of blood. The problem here is with filling because it's a stiff ventricle, and so it's a problem with ventricular diastolic. Uh huh. So heart failure. As I said, it's not a clinical diagnosis by itself. It could be caused by different things that it's useful to have on appreciation of what could cause heart failure with reduced or preserved ejection fraction. This is probably more relevant to any clinical medics watching, but you have reduced ejection fraction. The most common cause of that is a previous diagnosis of severe coronary artery disease or myocardial infarction, as in this woman on dilated cardiomyopathy. Remember, the heart is a floppy bag. Anything which causes a dilated cardiomyopathy will give you a heart failure with reduced ejection fraction. Um, one of the most interesting wants to come out of this is at the drugs. So when I say drugs, the most common class of drugs that caused this or actually chemotherapy drugs were increasingly saying, seeing that cytotoxic anti cancer agents cytotoxic anti cancer drugs are causing post chemotherapy dine aged cardiomyopathy. So these are the anthracycline drugs, or things like doxorubicin daunorubicin. Um, also peripartum. So women in the third trimester of pregnancy, or in the first few months after giving birth control, eloped. This damage it cardiomyopathy. I mean, they finally valvular heart disease. Um, say, for instance, your mitral regurgitation on the other side of heart failure with preserved ejection fraction, the most common cause is hypertension. And if you work through the physiology, this makes this makes a lot of sense because if you have hypertension, you have a higher after load. The heart has to work really hard to keep on pumping blood from the left ventricle into the aorta. So what it's going to do, it's going to start hypertrophy. And this is going to be a call center in chiropractor fever. Add sarcomere in parallel. You reduce the Lumen of the ventricle. But the force we wish it contracts that you have an increased proportion of the blood being injected out. So it's a heart failure with the injection fraction. And then you have other things like uh, the, uh, hypertrophic and restrictive cardiomyopathies. Infiltrative disease is requesting to be common and valvular heart disease, the most common valvular heart disease that gives you heart failure with preserved ejection fracture. Anyone know aortic stenosis on gets really similar to hypertension. So in hypertension, the problem is in the sort of I like to think of it as the distal aorta. You have I arterial BP that you're pumping against. The problem with aortic stenosis is a very, very start of the old days. They have a big bowel of instead of a normal size. Or if it's a really small orifice, the pressure that you need to develop to pump against that is high. And so you have the same down street with all of your results. This is something this, like, just talks to talk you through the pathophysiology of it. This is something that, in all honesty, we'll never need to know the clinical practice. I don't think, but understanding this framework really helps to put in context how the drugs we give actually work. Uh, because I'm really so poorly understood on don't think this is, um you explain to you after, so you do want a home. But if anyone is interested, um, I like to think of heart failure using these guys 10 cups. So if you look at the diagram on the right. Um, there are two curves in red and to come simply Sorry. Sorry. If anyone has red green color blindness yet, um, you have points A, B, C and D focus on point A. For now, this is showing more healthy person would have remembered the cardiac output on a venous return Have to be equal in the long term because the heart can either create nor destroyed blood it contains, so I really would have to be to be basis. But over the long term, because of the Franks starting mechanism, however much blood you get into the heart, it will compound and say, uh, can you copy? And Venus, We don't have to be equal for a normal, healthy individual to increase their cardiac Alpert. What you do is fluid retention, okay, there and the kidneys, that so that increases the need, systemic feeling, pressure. And so the blue curve shifts upward, and you can see that we go from point A to point B at any point. B. You see, the cardiac output has increased quite substantially almost by 50%. But look at the right atrial pressure. It's increased barely. There's there's not much of an increase. Their It's all, however, what happens in a patient with heart failure because of some pathology. This is, Remember the contribution pathology. They are in heart failure. They're cardiac output curve. So the red curve is has decreased and say we represent That's a curve that is fallen down. Look at their cardiac output now at points. See, it's really, really low. And this is a person with, ah, heart failure with reduced ejection fracture kit. Um, but they're kind of happens. Quite let. So what's the body going to try and do? If they're cutting, help is going to be low. The body will try and retain fluid. This is the normal physiological response of the body. But the body doesn't know that this is because of the patient having heart failure. The body just tries to increased cardiac out. So again it shifts the car up with the blue curve goes up. But now look what happens A point deep. Your cardiogram hasn't increased at all. If anything, they might have even slightly decreased. But the right atrial pressure. The central venous pressure increases massively, and so what? You now have is an increase in the venous pressure. And if this happens on the left side of the heart, you get blood backing up into the lungs and make you this cause a pulmonary edema. The patient will be really breathless, and this can. This can be fatal if it's untreated. And if it happens on the right side of the heart, Blood backs up into the peripheral circulation and you get things like a packet congestion, splendid congestion, renal congestion, peripheral edema. That's why the patient, we prove, that presented the pain the patient from the case number three she presented with bilateral swelling of her legs. So what you can see is that a lot of these problems really arise from the body's own response to try and increase cardiac output. So if you can find Mycological target these endogenous mechanisms, they can be really effective on the big pharmacological. Do we have for that in acute context, the's the diarrhetics? We could also give a sedative. It is an angiotensin two receptor blockers and a few other drugs, which are just brief you mentioned yet so diarrhetics. You've probably done this to death, basically, diarrhetics they increase the amount of urine that you passed out. Um, you have different class of diuretics. You have the loop diuretic. You have the thiazide diuretic on the cape of sparing diuretic. You also have the company had hydrazine hitters and the osmotic diuretic. So but then I'll really used, um, the heart failure. Nowadays, these are the major classes of drugs. But how did they treat heart failure? Well, again, it goes back to what we said earlier. They're reducing the extra sail of fluid volume. The mean systemic feeling. Pressure is reduced, the pre load is reduced, the cardiac output goes down. It's very, very slightly. But remember, because the premium is reduced, your reducing the work that the heart has to do the right atrial pressure goes down any eventually you're going to reduce the BP response. So you're reducing the after load of the amount of work that failing heart has to do. This is just a diet. I'm showing where they work. Ignore the carbonic anhydrase inhibitors. For now, acetazolamide is the only one you probably need to know. For one, be motive. It's used to treat altitude sickness on be used to treat cerebral demon. In some cases, it's not really use that often for heart failure. Loop Diuretics are really powerful furosemide you should know about on There are in acute context. They're really useful, uh, fire sites on the so called friends. I'd like diuretics act on the NZC to the sodium chloride coach runs water, and then we have a taxi, um, sparing diuretic. So it's worth noting that potassium sparing diarrhetics come in two types. You have the backing him. It's a fist of these things, like Triam tree and and a little right, which actually block the epithelial. Any questions on then you have what's really, really useful. Nowadays we have these drugs called mineralocorticoid receptor antagonists on these guys that end in known so spironolactone on heparin, um, they had target eyes, the mineralocorticoid receptor, the action of out of steering decreases. And remember, our stereo is a steroid on it. It works by. It works by how are the steroids works of it? It ultrastrength in on, so you get less sodium potassium parts being trying to form of a basal lateral memory, fewer SK channels on the apical membrane and fewer, um, imax on the apical member and as well. And in the long term they were. They will cause a cable sparing diary cyst that's really important. The other big class of drugs of a sudden here it is an angiotensin two receptor blockers. Clinical trials have shown time and time again that angiotensin two receptor blockers on a sin hip. It is are amazing drugs at reducing both morbidity and mortality in patients with cardiorenal pathology. Um, they are used for a whole host of my thought is they are used for heart failure. These angina and all that they can be done is for high potential. If you're a type two diabetic or if you're under 55 on, you want to treat someone, do you put them on a CD? But they have really good outcomes. These are the drugs that ended up. Really. Ramipril is the most important one on you know. They, in terms of the mechanism of action, is really in the name a syndicate hours inhibit, and your Rattigan's I'm and a are these blocks the receptor. It's way more important to you guys to know about the renin angiotensin a little steroid system. The drug state because, um and your attention to is like is a potent. It doesn't lot of things which, if it happens in excess, can lead to hypertension on behalf. Failure does. Does anyone want to say some of the things that angiotensin two does? Yeah. Intensity does. Yeah. Yeah, Exactly, Andrea. Attention to again. This is something that you do in one a home. I think you might not have done it, actually. And this might be in Lent. Uh, on. It's really like understanding arena and just tension. Aldosterone system is the probably the single best thing you can do to, like, understand your cardiovascular pathophysiology and pharmacology. This system is dysregulated in a lot of people with heart failure and your turns into someone's mentioned. It's amazing constrictor, um, angiotensin. And you're meaning blood vessel tensing. Meaning, um, I didn't do last little Greek whatever, but it probably needs to, like, come strict or yes, it's a vasoconstrictor of potent basic constrictors on it stimulates, and it's anti natural heretic on anti diuretic, so increasing the amount of sodium you retain the water. It's also a powerful dipsogenic increases the amount of water that you drink A, um stimulates first. It also stimulates your appetite. Assault. Remember, salt is a risk factor for hypertension, specifically because the more salt you retain, the water you retain, the higher your mean systemic feeling pressure the high your venous return, the higher your cardiac output on because of the fact starting records of the higher the arterial BP will be a swell Thea. Other thing that angiotensin do does is it stimulates the production of our dose steroid and you're tempted to act on the cells of the zonegran very low, said the adrenal cortex. Simplest, the production of a little steroid. And as we said earlier, aldosterone will increase the amount of potassium that used to create festival, but also the amount of sodium that you retain. So what we're doing is my antagonizing and your attention to your really stopping all of these effects. And as we work through the mechanisms for the past 11 of ours, this will treat Hypertension is good for treating angina. And those are really good for treating coughing, um, increasingly weak. And we're also using other drugs S O B two blockers. As I said earlier, be two blockers, long term agonist um of beat adrenoceptor is is associated with cardiomyocyte, a pop Tosis. If you antagonized beat, beat and Rena sectors, you're reducing that. And so you're reducing the strain on the heart. A new class of drugs that's come about is these drugs for our knees or ARNI? Zombies are angiotensin receptor blockers and neck rely, said inhibitors. Now there's a bit of it. It's not really not really a single drug, but they're actually combination drugs. Black. So Smith brand of doing that? One of them, we call them. We call it interesting. It's a combination or valsartan, which is an angiotensin two receptor blocker, which we've talked about on Saturday. Atrial. Now, some cubit troll is a neprilysin inhibitor. Um, for license, um, is an enzyme that degrades natural heretic peptides. You may have come across atrial natriuretic peptide. You man come across brain or be type one trick you and actually retic pep type. The tree arrested peptides are released when the heart is an increased strain or there's been tricky little meditation, and they promote a natural heretic diary sets. So again, if you inhibit neprilysin, you're increasing the circulating concentrations of A M P and BMP, you're increasing the amount of salt that you excrete, and by extension you're increasing the amount of osmotic diuresis that you achieve. As a result, you're reducing the pressure and you're reducing the strain on a failing heart. Interesting history of really good results in clinical trials, and it's likely in the next 10 15 years will be using that a lot more in clinical practice. It wasn't reading inhibitors be in trouble because, remember, I said earlier, they will reduce the amount of reading that you actually produce from the just of memory cells. You could have directed images of readings, and Alice Kyron is the most is one of them. Then you have these drugs SGLT two inhibitors. SGLT two is expressed in the real tubules where it absorbs. It's a sodium glucose transporter. It absorbs sodium any absorb glucose. So originally, this these inhibitors so these are the blood flow is is the top of your flows in and packet flows in, uh, they were developed. Teo. Increase the amount of glucose that you excrete urine on their four. Reduce the amount of blood sugars to be reused for treatment of Type two diabetes mellitus. However, these patients were put on a clinical trial, and what they found was that it was really good for treating Type two diabetes. But these patients, uh, didn't end up in hospital with cardiovascular pathology, and they didn't die of heart disease as much. In fact, there was significant reductions in cardiovascular morbidity and mortality. So then they did a trial on what they found is actually SGLT. Two inhibitors are amazing people with heart failure. We don't exactly know why it's really good for heart failure because we're not sure about the role of SGLT two in the heart. Um, but what we do know is that these drugs are again increasingly going to be used in clinical practice, the final class of drugs for heart failure. They're really red, but they're the ER is, or vasopressin receptor antagonists based on pressing is a th on anti diuretic. Or, you know it's another name for anti diuretic or men. Is arginine vasopressin on anti diuretic or mean again? It's mechanism. It does exactly what it says on the 10th anti diuretic hormone. It reduces the amount of urine you produce. A war fluid is retained, an increase in blood volume will be. The main goal of 88 is to, um, is to decrease plasma osmolality, but also, it has a small effect on increasing BP. So if you actually antagonist the receptor, uh, you're going to reduce the blood volume. You're going to reduce the pre load on a failing heart on example of this is told that time, which, incidentally, is a good drug for treating some patients with polycystic kidney disease. Anyone's interested on the final case really is hypertension. No, you probably know why it's important to treat hypertension. Well, it's because hypertension is a clinically silent disease, which means that, um for many years, So I'm talking meant, like tens toe tens of years. Uh, it doesn't really. You didn't really notice it. Like someone gonna have hypertension for 40 years. Nothing happens, but the problem is wearing it when it's been around for 30 to 40 years, you have these long term adverse secondary to these consequences of really bad. This this increase the risk of stroke of my cards of infraction everything. A bit of a misconception, is that it causes blood vessels to burst. That's not strictly true, because unless you have a specific problem with the blood vessels themselves, you would need pressures of 300 millimeters of mercury to cause them to bust, which isn't really achieved in hypertension. However, if it happens for a really long time, you do get both microvascular and microvascular damage. I encourage you to look this up a swell if you're if you're interested because, um, high potential Uh, it's especially for one b motor. They love an s. A question on this. If anyone does one be murder here yet, see, in terms of drugs we used to treat hypertension, we've already talked about all of them because we've talked about the pathophysiology of all these conditions that we talked about the pharmacology of all of them say a plane. Your understanding. You'll know exactly why we use all of these other drugs. As you can see, the drugs that we used to treat hypertension a sentiment is and you're tempted to receptible. But we've already talked about why they work. They reduce after load. They reduced the strain that the heart has to pump against. They reduce the total proof for resistance calcium channel blockers, a vasodilator and vessels. They reduced. Try to approve for resistance by as I'd like. Diarrhetics diarrhetics reduce cardiac output has already reduced the fluid volume and, by extension, already scarred. A helper. Reduce the at your BP. Spironolactone. Another diuretic. Remember, it's a potassium sparing diuretic mineralocorticoid receptor antibody. Be sure because we've talked about potassium channels because we talked about We haven't talked about how the blockers on, but they are just antagonised of GQ. Couple out for one, adrenoceptor is true, um, because of vasoconstriction. So by antagonizing, then you reduce the amount of constriction of blood vessels. You'll reduce general peripheral resistance, and you will reduce the pressure. So these are the major classes of drugs on for treating hypertension on then, all of the drugs that that we've talked about here are used in clinical practice. So a send him it says Ramipril is prescribed left, right and center, and you wanted to receptor blockers. Losartan valsartan a comment Calcium channel blockers. We've talked about my favorite be as a dihydrate, Periodi, CCB, Verapamil and Diltiazem, a less commonly used for hypertension. Because remember what we talked about earlier, and they tend to act war on the heart size I'd like diuretics, which is indapamide, and the total is own. That's something Peter blockers atenolol by Sapporo, maybe carvedilol on the Livalo. If I trust it's prescribed them. Alpha blockers aren't really used that commonly anymore and cable channel over this again. They're not really that. You think it's still interesting to know about the mechanism, especially for one be murder. So that is the end. Uh, appreciate it was really long. Um, but I hope that that's giving you a really good on this, um, overview of the clinical applications and why the things you learn in home bored and mode and to do with the heart on the cardiovascular system are important in clinical practice. You got any questions you can ask me now or you can email that email. Me? Um, my email is operating the chapped. Yeah, that's my email if you want to. Um, yeah. Also thank you for that was, that was amazing. Hopefully, your old building audiologists now, and hopefully you'll be doing cause surgery and pop worth at this point, please do for them the feedback. It's really helpful for both admit smoking, also 15. As because it's obviously useful for his ball for you in the future. So please do feel it in again if you have any questions for every day they just dropped in the chart now or send it over to his email on the chat. Otherwise, you can also just email me and I'll pass them over to him. But if you don't have any questions, uh, you're free to escape and enjoy Christmas and we'll see you. We'll again, then you have everyone by.