DIP Episode 63 - Cardiac Pharm Part 3 (The Final Part)

Okay, welcome. My name is a divine. I am a PGI one a transitional year resident and this will be the 63rd episode of the Divine Information Podcasts and we are going to be finishing up cardiac pharmacology today. Today's Thanksgiving so from the bottom of my heart I wish all of you happy Thanksgiving. Again, regardless of whatever may be going on in your life I remain thankful. I mean I'm on my ICU rotation right now and I've seen people die, I've seen people have to spend the Thanksgiving in the hospital which is not the most ideal situation. So just be thankful. Okay, remember as long as you're alive you have hope. Right. Again I tell people that a living dog is better than a dead lion. Right. So I'm just gonna have hope you know do your best. Trust God and things will work out for the best. Okay. So let's begin. So cardiac pharmacology right so today I want to start by you know seeing some differences between three drugs that are sort of like close cause ends nitroglycerin nitro-perside and hydrozim. Okay. I think those will be helpful. I'll talk about like commonalities and differences. Right. So the thing is when you think of nitroglycerin think of it primarily as a vino dilator. If you think of an nitro-perside think of it primarily as a vino dilator. And an attirula dilator think of it in those two domains versus hydrozim that is primarily an attirula dilator. Okay. And the thing is the mechanism of action of hydrozim is kind of unclear. Right.

But for nitroglycerin nitro-perside basically think of them as nitric oxide precursors. And the thing is remember right if you want to make nitric oxide you start with arginine. So nitro just this is just more missing about the biochemal correlate here. Remember nitric oxide can be made from arginine. I remember arginine is a part of the urea cycle. Okay. So you make the nitric oxide and basically the nitric oxide is made in endothelial cells from arginine. And then it diffuses to smooth muscle and it can activate guanilite cyclists. Okay. Guanilite cyclists helps you make cyclic GMP. Okay. And then that's it. GMP just like cyclic AMP activates protein kinase A. cyclic GMP will activate protein kinase G. And then when you activate protein kinase G. Protein kinase G activates myocene-like chain phosphatase. Okay. Because remember right if myocene is phosphorylithet it's active and you have muscle contraction. But the thing is for these drugs to be dilators obviously they must be causing smooth muscle relaxation. So the thing is you need to defosorylite myocene to render it inactive. So that is where myocene-like chain phosphatase comes into play. When myocene-like chain phosphatase is activated by protein kinase G. Okay. Myocene-like chain phosphatase becomes active. It diffusorylits myocene and you no longer have contraction of smooth muscle. So you have relaxation. Okay. So very high you to know this.

And actually please don't forget that PDE5 phosphodiesterase 5 inhibits, I mean breaks down cyclic GMP. Okay. So think about if you were to inhibit PDE5 you no longer break down cyclic GMP. Okay. So you have potentiation of the effects of cyclic GMP. And you have this or dilation. For example, you could have dilation of the blood vessels that feed the penis and that can cause that can help with erectile dysfunction. That's how drugs like cell dental fill and dental fill work. Okay. And one other high you thing to know is because mitroglycerin is primarily a venodilator, right. It decreases preload, right. Because again, it basically increases the capacitance of your veins. And by increasing the capacitance of your veins, your veins storm or blood, right. Less blood goes to the heart preload decreases. And because your preload is decreasing, you are decreasing myocardial oxygen demand. Because the heart does not have to work as hard to pump blood. That is actually the primary mechanism of action behind nitroglycerin being good for ancient amino people think, oh, it dilates your coronary vessels. It does. Well, that's a very limited mechanism of action. The primary mechanism of action is to decrease your myocardial oxygen demand. Okay. And then for nitropercyte, I want you to think of nitropercyte as being primarily used for hypertensive emergency. Okay. It lowers your blood pressure very quickly. Okay.

Because it's both a venodilator and a nitrile dilator, it decreases both preload and afterload. Okay. And then hydrolyzing because it's primarily a nitrile dilator, it decreases afterload. And then with nitropercyte, one high you thing you want to remember is that it contains cyanide. Okay. And then you can remember, if you have watched the bio-camera review video, remember that cyanide can bind to complex four of the electron transporching. And by binding to complex four of the electron transporching, you basically decrease ATP production. Right. And you can basically go into an energy crisis with a cyanide toxicity. And I mean, obviously the way you fix this as I believe I've discussed in a previous podcast, what even the bio-cam lecture is you give ammo nitrate. Right. The ammo nitrate will convert Fe2 plus to Fe3 plus. Right. So the fearsome of iron to the very form of iron because Fe3 plus basically is, if you think of Fe3 plus, Fe3 plus is very good at binding cyanide. Okay. And remember, right. Hemoglobin contains iron. And usually hemoglobin contains iron in the Fe2 plus from the fearsome form. That's the form that can bind oxygen. Okay. When you have heme and globin containing iron that is in the 2 plus form, that's hemoglobin. But when you have heme and globin that is bound to iron in the 3 plus form or the ferric form that is met hemoglobin, that form cannot bind oxygen. That form of iron actually cannot be reabsorbed in the doorknob. Okay.

So Fe2 plus is a preferred iron, but Fe3 plus is good because it helps you make, it's very good at binding cyanide. It's very good at binding cyanide. Okay. So that's why if a patient has cyanide toxicity, right. You give them in one nitrate. It's a pathologsy, dyes in in general, convert the Fe2 plus to Fe3 plus. That binds of the cyanide and then you give thiosol fit to convert that complex into thiosyanate and then you peel or poop it out of the body. Okay. And just as a quick reminder from biochem, remember that there is an enzyme known as methemoglobin reductates, converts Fe3 plus to Fe2 plus. Okay. Methhemoglobin reductates is actually activated by meththalene blue. That's why meththalene blue can be used to treat methemoglobinemia. And then don't forget with hydrolyzing, because it decreases your afterload, your heart rate would increase, right. Because it's sort of thing of it as a reflex tagic cardio. If you decrease afterload, the way your heart rate, that would decrease blood pressure, right. So the way your heart responds, pair your bar receptor response is to increase your heart rate. Okay. So you get a strong sympathetic discharge from the brain. I mean from the brain stem, that causes your B1 receptors, your beta 1 receptors to fire more. Okay. So the thing is if a patient is getting hydrolyzing, you can actually blunt that reflex tagic cardio by giving a beta 1 selective blocker like a tenelon to blunt that effect.

And then don't forget that hydrolyzing is associated with a with a drug in Guil's Lupus, right. So don't forget your anti-Histonantibodies. And then your PDE inhibitors, right. So your phosphodiesteries inhibitors, I will say for step one, there are probably three groups of PDE inhibitors you want to know. You want to know your PDE3, your PDE4 and your PDE5 inhibitors. Okay. And again, all these drugs, because the inhibitors phosphodiesteries, they increase, at least for PDE3 and PDE4, those increase your levels of cyclic AMP, for PDE5, those increase your levels of cyclic GMP. So PDE3 inhibitors, right. The big ones you want to know, you want to know your cellostrozole and diperidomol. Okay. Those are actually anti-plet lead drugs. But remember I've talked about this in prior podcast, cellostrozole diperidomol. Those are powerful. They're especially cellostrozole, it's used for peripheral arterial disease, because as you'll see, in fact, I guess I'll go ahead and talk about this now. The thing is, high levels of cyclic AMP do two different things. If you're talking about cardiac muscle versus smooth muscle, okay. High levels of cyclic AMP do two different things. If you're talking about cardiac muscle versus smooth muscle, in cardiac muscle, increase levels of cyclic AMP, actually promote contraction of cardiac muscle. But in smooth muscle, high levels of cyclic AMP promote relaxation of smooth muscle. It's very, very high yield to understand that.

Because if you understand that, then you should know that if you give cellostrozole, which is a PDE3 inhibitor, and your levels of cyclic AMP go up. Back and cost relaxation of the smooth muscle that line the blood vessels that are in your low extremities, that's why cellostrozole can be used for the treatment of peripheral arterial disease. Diperidamol is a PDE3 inhibitor. It's used in the pharmacologic stress test that takes advantage of the coronary steel principle. I've explained this coronary steel principle so many times in previous podcasts. I'll encourage you to go back and listen to those. Basically, in the coronary steel principle, you try to dilate vessels so that you can still blood away from maximally dilated stenosed cardiac vessels, right. So to dilate those vessels to activate the coronary steel principle, you use a PDE3 inhibitor like diperidamol to dilate blood vessels. Because by inhibiting PDE3, it bumps your levels of cyclic AMP. Another drug known as Mewrenone is a PDE3 inhibitor. It's used a lot in cardiology. It's an awesome drug because it does to thin. It's used to treat heart failure. One reason it's good, you can even use it in shock, is again, by inhibiting PDE3, it increases your levels of cyclic AMP in cardiac muscle. It's a positive I know trop. It encourages cardiac muscle contraction. But it also increases your levels of cyclic AMP in smooth muscle. It decreases your afterload because it's relaxing smooth muscle.

In doing that, it's basically increasing your cardiac output and actually decreasing the resistance to flow of blood out of your heart. In fact, some physicians call Mewrenone an I know dilator, right. Because by increasing cyclic AMP in cardiac and smooth muscle, it basically makes it easier for your heart to pump blood. And then it removes the blockage to the flow of blood out of your heart by decreasing afterload, by relaxing smooth muscles and causing a decrease in afterload, right. Because it's dilating your blood vessels. Now, your PDE4 inhibitors, again, these drugs increase cyclic AMP. So you should already know what they will do to smooth muscle. They will cause relaxation of smooth muscle. For example, the smooth muscle in your airways, right. If you give a PDE4 inhibitor, your cyclic AMP levels go up, you relax the smooth muscle of the, that lines your airways, like your trachea and stuff like that. And you get bronchordialization. That's how drugs like the Ophelin. Fiofilin is a force for diastere is inhibitor. And the reflumilast, reflumilast is a drug that's actually used to treat COPD, like NSTCOPD. So, again, magnesium of action makes sense because you want to open up herways for those people. And then your PDE5 inhibitors already talked about that drugs like cell-denafil, tadalafil, the increase your levels of cyclic AMP. They used to treat erectile dysfunction.

In addition to that, they also used to treat pulmonary hypertension, pulmonary arterial hypertension. Okay. So, next thing I'll just talk about, just kind of a grab bag of things before I go into the anti-lippid, the anti-fat medications. But basically, to set the point, to set the point, remember you give MAG, right. And the thing is MAG, no one really knows how MAG works. But MAG is used for many things, right. I should know for you exam. One is you can use MAG for Tosatoquan. Remember, it's a kind of polymorphic ventricular tachycardia, and it can arise in the setting of a cutie prolongation. You can also use MAG as a topoletic, okay. Because the thing is MAG can actually decrease the contraction of the uterus, for you know, like two to three days. So, if you want to delay pregnancy, let's assume MAG is about to deliver a preterm baby and you want to give like steroids to promote fetal long maturity, you can give MAG to sort of slow down the pregnancy prevent contractions for a few days, okay. For the fetal long tumor trut, at least to get your two doses of Bethamethasone, okay. And then don't forget that MAG is also the treatment of choice for a clumsy, right. Where a patient is having seizures, or even as perphylaxis, if a patient has like preeclumsia, right. Before they get to that stage where they have seizures, you can give MAG for that. And then don't forget that MAG also decreases the risk of cerebral palsy, okay.

So, this is more for your third year, but it can be like a bizarre question on step one, right. So, if a mom is about to deliver a baby and it's less than 32 weeks, you can actually, basically the buzzword is neuroprotection. You can decrease the risk of cerebral palsy in that kid by giving magnesium. Now, magnesium also has some effects on PTH actually, right. So, the thing is, if you have very high levels of magnesium, think of it as having very high levels of calcium. Your PTH release will be decreased, right. So, high MAG levels decrease the release of PTH, okay. But, for low MAG levels, there are two things you want to know. You want to know if you have low levels of MAG or super low levels of MAG. When you have low levels of MAG, okay. That is like having low levels of calcium. Your PTH release will be increased. But, if you have super, super, super low levels of magnesium, that actually also decreases the release of PTH. So, let me summarize. If your PTH levels are high, I mean, sorry, if your MAG levels are high, you decrease your release of PTH just like you do for calcium. If your MAG levels are low, you will increase your release of PTH just like you do for calcium. If your MAG levels are super, super, super low, you will actually also decrease your release of PTH, which is paradoxical. And then, one other thing I want to mention, right. If you have hypomagnesiac, remember you can get a QT prolongation from that. Remember the rule of mention many times.

That if you have any high notable hypodessoder, that can cause QT prolongation. Like hypokalcemia, hypomagnesemia, hypokillemia, right. Those can all cause QT prolongation. But, one of the high youths that I want you to know is, if your hypomagnesiac, you will not respond to potassium and calcium supplementation. So, classic exam question, patient is hypokalcemia giving, giving, giving calcium. Their calcium levels are not increasing in the blood. The reasoning behind that is because they are hypomagnesiac. So, your next step in management will actually be to check their levels of magnesium. Because the thing is, if a hypomagnesiac makes, it causes your kidneys to waste a lot of ions, especially calcium and potassium. So, you want to repeat those people's magnesium levels and then things will kick back into gear. And one telltale sign of magnesium toxicity is when you have decreased tendon reflexes. They classically make this an OB question on exams, right. So, like an OB-GYN question. So, they tell you about a patient that has preclamsia, they are an amagnesium infusion. And then they say like, what's the next step in management, right. You want to do periodic checks of their deep tendon reflexes, right. Because that's like the first sign of magnesium toxicity, decreasing your deep tendon reflexes. If you don't catch it and your mag level will keep going up, okay. You have respiratory depression.

If you don't catch it then and then your level will keep going up, they will go to flat lines, right. Assist still, okay. And then that's, I mean you're dead, right. If you're an assist still, right. So, you want to watch that. And actually the way you reverse magnesium toxicity is also with calcium gluconite. Remember calcium gluconite is also the first drug you give if a patient has hyperchillinia to protect the myocardium. Any calcium containing compound can reverse mag toxicity. And then some other quick things about blood pressure. I've mentioned this before. But if a patient has BPH and hypertension, right. You obviously want to give an alpha blocker, okay. Because that would open up the bladder neck but also dilute their blood vessels and reduce blood pressure. Right. But if you only have BPH, you want to give Tamsulocin, right. Tamsulocin. It's also an alpha one blocker but it's an alpha one AD blocker which is the one you only find in the bladder, okay. It does not affect your blood vessels. Now, if a patient has hypertension and diabetes, right. Obviously you want to give ACE inhibitors or AR Bs, right. Now what's the mechanism behind that, right. The thing is if a patient has diabetic kidney disease, remember diabetes affects the glomerular capillaries. But remember that it also causes a non-inzymatic glycosylation of the efferent, not efferent, efferent arterials, okay. The vessels that drain blood from the glomerular capillaries.

So the thing is if you cause non-inzymatic glycosylation of the efferent arterial, you basically constrict those efferent arterials and that would increase your GFR. Like sort of think of it as like a permanent problem. If your efferent arterials are always like conastinose, you will raise the hydrostatic pressures in your glomerular capillaries, that will increase your GFR, right. The thing is if your GFR is not meant to be high all the time. It's supposed to be regulated, right. You never want to be at the extreme end of anything in life all the time. You want to be like, you know, sort of kept within a relatively constant range. So if your GFR is always high, now ultimately damage your glomerular capillaries, right. That's something known as hyper-filtration injury. You're getting that hyper-filtration injury because there's intra-glomerular hypertension, okay. Hyper-filtration injury from intra-glomerular hypertension. So that can over time cause damage, right. And then you begin to have microbominuria and then again, microbominuria and then you're going to end stage kidney disease as a diabetic, okay. And again, if you have diabetes and you have microbominuria, you need to be put on an isine inhibitor. So on ARB. So even if, and the reason those work, right. Remember that angiotensin II causes construction, right. So when angiotensin II acts on receptors, it causes a construction of the effranatural.

So if you give an isine inhibitor on ARB, you'll basically remove the effects of angiotensin II. So instead of having, instead of having construction of your effranatural, you have dilation of your effranatural and that will lower the hydrostatic pressures in your glomerular capillaries. And that will basically cut down or slow down the rate of degeneration of the glomerular capillaries in diabetes, right. And don't forget though, right. If you're lowering that hydrostatic pressure, you should already define that, actually that's the correcting issues of the term. But you should already imagine that the, the GFR will go down, right. So that's why isine inhibitors and AR Bs are kind of contraindicated in people that have bilateral renal adristinosis. Because it's inhibitors, AR Bs, when you give those things, the GFR goes down so your creatinine goes up. Okay. So again, if you have diabetes, I have microabluna, even if you don't have hypertension, it doesn't matter. You need to be put on an isine inhibitor and ARB. This is a very common question in 30. So I guess we can jump into the anti-lippid medications. I guess while we're on that topic, because I don't really see anywhere else where I could, you know, throw this in. So it probably makes sense to, you know, go ahead and discuss it now. But basically one drug I think I want to mention is only stat. Only stat is used as well with low stroke, right. It's an inhibitor of pancreatic lipase.

It also inhibits gastric lipase, right. By inhibiting lipase, you don't break down fat, you don't reabsorb it, right. And then you basically put it out. But obviously, right, it's Tia Doria, right. And like diarrhea will be like side effects of poorly stat. So this one of those rare things you want to know, you want to know. And then that weird thing is it also, apparently, inhibits fatty acids and things. If you inhibited fatty acids and things, you don't make fat. And again, you don't build up fat in the body. This one of those rare things you want to keep at the back of your mind. So, but is anti-lippid medications people are like, oh, divine. There are so many of them, so hard to understand. But the thing is, what of them makes sense, right. So I feel like, and I know I've done this, I believe I've done this in my bio-chemist video. But I'm going to do it again real quick here for like five minutes. Talk about the biochemistry of lipids. If I talk about that, I think you'll make it much easier for you to remember and understand these anti-lippid medications, right. So, quick spill on the bio-chemist of lipids, right. So let's assume you consume fat, right. When you consume fat, you release lipids from the pancreas, right. That lipids will break down the triglyceride, you just consumed into mag, so monoacyoglycerol and two-three fatty acids.

And then with the help of bowel, you basically will absorb these monoacyoglycerol and the two-three fatty acids into the entire site. And then inside the entire site, right. That mag and the three fatty acids, they are made right back into a triglyceride. But the thing is, that triglyceride cannot just, you know, travel on its own in the blood. The thing is, that triglyceride is bonded with cholesterol, right. To form, to form something called a cholesterol ester, right. So, if you remember from origami chemistry in college, right. If you have a reaction between a caboxylic acid and an alcohol, right. It's like a condensation reaction, you form an ester, right. So, cholesterol, all has an alcohol group, right. And then you're having a fatty acid, which is almost like a caboxylic acid reacting with it. So, that's why you form a cholesterol ester, okay. And the thing is, the enzyme that makes that reaction work is known as ACAT, okay. ACAT, right. So, ACAT is like, I think it's like, acyl, co-a cholesterol, isotransferase, or ACAT for short. So, ACAT makes that reaction happen. And then, before that cholesterol ester leaves the GI tract, right. And partners output, APOB48, okay. Remember, like the APOB48 is made by alternative splicing from APOB100. It's just one of those weird biochem things, they can sort of, I mean, cell biology things, they can sort of slide into your exam, okay.

And please don't forget that APO, one key enzyme that helps you make that APOB48 is something known as MTP, micro-somal transfer protein, okay. Micro-somal transfer protein, protein helps you make APOB48. Okay, and don't forget also that alternative splicing is how you make IGD, okay. That's how IGD is basically a derivative of IGM, okay. You make that bio-somal transfer splicing. So, the cholesterol ester plus APOB48 together is what's known as the chylo-micro, okay. And one quick thing I'll just sort of say here is that HDL, HDL, the molecule, has four things with it, okay. In fact, HDL is a combination of four things. Number one, APOE, number two, APOC2, number three, L-CAT, and number four, APOA1, okay. So again, I'll mention that again. HDL has four components, APOE, APOC2, L-CAT, and APOA1. And the thing is that APOE and APOC2, HDL do need seats to other things, as you'll see, as we go along. And then that L-CAT is kind of an enzyme that HDL uses to either make itself and also to collect cholesterol from the peripheral, okay. So sort of clear your system of cholesterol. So, let's continue this chylo-micro-story, right. So HDL, as I already discussed, donates the APOE and APOC2 to the chylo-micro, okay. And then that chylo-micro encounters an adipocyte, okay. And the other side, they have a membrane enzyme known as LPL, lipoprotein lipids. That lipoprotein lipids helps you cleave the chylo-micro, okay.

And when it cleaves the chylo-micro, the thing that you are left with is something called the remnant of the chylo-micro, or the chylo-micro-rennant, right. And that chylo-micro-rennant has APOE, okay. Why do we need that APOE2 from HDL in the first place? The thing is, APOE2 is a co-factor for LPL, for lipoprotein lipids, okay. Lipoprotein lipids' job is to break down the triglycerite. Because the thing is triglycerites cannot be reabsorbed across the membrane of enterocytes. So, you need to break them down outside the adipocyte into monosyoglycerol and two-free fatty acids. And that's done by lipoprotein lipids, okay. And then, when you break them down, you reabsorb them, and then you re-make them into triglycerites in adipocyte as well, okay. And again, the enzyme that makes that happen is lipoprotein lipids. So, think about it. This process involves your storing fat, so it should make sense that insulin operates the activity of lipoprotein lipids. Okay. So, you're from the triglycerite in the cell, right. And then, basically, the chylo-micron remnant is still has EPOE. It travels with that, okay. And then there is an EPOE receptor on the surface of the liver that binds to that EPOE on the surface of the chylo-micron, and accepts that chylo-micron back into the liver, okay. That's the end of the root for the chylo-micron. Although, remember, the chylo-micron can travel through your lymphatic system, right.

So, if you're transsect like lymphatic duct, like your thoracic duct, that can cause a particular kind of plural of fusion known as chylo-thorax, okay. Chylo-thorax. Now, but the thing is, it's not only your entire sites that can deal with triglycerites, right. The thing is, your hepatocytes, your liver cells can also deal with triglycerites, right. But again, same story, just like we had in the entire site, right. That triglycerite cannot travel on its own, right. It's bound to cholesterol. It's made into a cholesterol ester. But the thing is, instead of getting married to EPOE 48, like we have in the entire site, we get the cholesterol ester that's made in the hepatocytes. Marys EPOB100, okay. Marys EPOB100. And the cholesterol ester made in the hepatocytes, because EPOB100 is known as VLDL, okay. VLDL. And then, again, VLDL, traveling the circulation, picks up EPOE, C2 and EPOE, from HDL. And then, on the surface of a depo site's EPOC2 acts as a co-factor for lipoprotein lipase. That breaks down, that basically helps you get rid of triglycerites from VLDL, right. And the thing you have at the end of that process is known as ideal, intermediate density lipoprotein, okay. And then, there is another weird enzyme in the body known as hepatic lipase, hepatic lipase. Again, hepatic lipase. That hepatic lipase takes that ideal and converts it to LDL, okay. And then, when you've made LDL, LDL then returns EPOC2 and EPOE back to HDL.

So you may see divine, but if LDL returns EPOE back to HDL, then how does it get back into the liver? Well, remember that LDL still has EPOB100? It so happens that there is an EPOB100 receptor. In fact, another name for the EPOB100 receptor is LDL receptor. That's found on the surface of hepatic lipase that you can use to clear hepatic lipase from the serum. I mean, they can use to clear LDL from the serum, sorry. So, and don't forget, if you want to make cholesterol, the red limiting enzyme is what? HMG-queeriductase, okay. They will try to put HMG-queous synthase on you. Please don't pick that. HMG-queous synthase is used in many pathways like ketone body synthesis. It's used in cholesterol synthesis, okay. But the red limiting enzyme for cholesterol synthesis is HMG-queeriductase, okay. Converts, it's valid on each to something. Okay. Now, so what are the fates of LDL, right? LDL has two fates, right? So, LDL, 80% of it is taken back to the liver, right? It's taken out by the LDL receptor. And the thing is, when the LDL receptor binds to LDL, right? Remember, another name for the LDL receptor is the EPOB100 receptor. When the LDL receptor binds to LDL, it brings the LDL with the cholesterol attached to it into the... It brings that into the... It brings that into the hepato site. And then, the LDL receptor is broken down by an enzyme known as... What's the name of this enzyme? What's the name of this enzyme? PCS-K9, right? PCS-K9, PCS-K9.

PCS-K9 breaks down the LDL receptor into like inactive stuff, okay? Bricks it down into inactive stuff. And one thing I guess I forgot to mention is that... LDL can actually accept cholesterol from HDL, which is not a good thing, because LDL dumps cholesterol in your periphery. You don't want that, right? HDL takes cholesterol away from your periphery. But the thing is, there's an enzyme that can take that cholesterol, take it from HDL and put it on LDL, which is a bathroom, obviously, right? And the thing that makes... Well, actually, it's not always a bathroom, right? Because LDL actually does some good things, right? Because your cells, your cell membranes, right? That are made of forceful lipids, knee cholesterol, right? It's when your LDL is high, that's bad, right? So, let's assume you had a disease where you have high levels of LDL, right? Like hyperlipidemia. You want to give something that inhibits that enzyme that makes cholesterol go from HDL to LDL. That enzyme is known as CETP, cholesterol, estrotransfer protein. They actually drugs that inhibit that enzyme, but I suspect that you may not... You will likely not see those on step one. Because many of those drugs have not really worked, although I think there is one, that recently sort of like made the cut and may go into like... You may begin to use it, you may begin to prescribe it to patients, right? I think they say that it will probably be like super expensive. But let's get back to this.

So, PCSK9 breaks down the LDL receptor in hepatocytes into something inactive. And then the other thing of LDL besides the 80% that goes to liver is the 20% basically dumps cholesterol in the periphery. So again, keep those two things in mind. Now, HDL, what's the deal with HDL, right? So, the thing is HDL, like I said, collects cholesterol from the periphery, converts it to a cholesterol ester. And it does that with LCA Ts. Just like ECA Ts help to make cholesterol esters in enterocytes. LCAT helps you make cholesterol esters with HDL. And LCAT actually uses APO A1 as a cofactor. Just like lipoprotein lipase used APO C2 as a cofactor, very high up to know that. And again, I've talked about the cholesterol ester transfer protein. So, now that you understand the biochem of lipids, then the pharmacology of lipids makes perfect sense, right? So obviously, the first drugs will start with the statins. The statins inhibit HNG query ducties. So, let's talk about the mechanism behind these drugs, lowering your cholesterol levels. This is something they love to test on step one. And also on step two and also on shelf exams, because something that people just don't get for some bizarre reason. So, these drugs are the best drugs lower LDL. And the thing is, how do these drugs work? The thing is, if you inhibit HNG query ducties, the levels, the intracellular concentration of cholesterol with hepatocytes goes down. So, the amount of cholesterol inside hepatocytes goes down.

So, when hepatocytes don't have enough cholesterol, they begin to freak out. Because the nickel cholesterol for many things, they begin to freak out. And by when they begin to freak out, they begin to express a lot of LDL receptors. So, when they express more LDL receptors, they capture more LDL from the circulation. And that basically increases the clearance of LDL from the circulation. Because the LDL has the cholesterol that the lever is looking for. This is, again, this is like, floridly high autonone. This is the primary mechanism of action behind statins lowering your LDL. The increase the expression of LDL receptors. You need to remember this both frees for your step one example. Now, classic drugs here, they all end in statin, atover statin, lova statin, prava statin, simva statin, rusover statin, whatever. Okay? So, let's say some more things about the statins. So, I said that ultimately, right? Mivalonitis involved in that cholesterol synthesis pathway. The thing is, Mivalonitis actually used to make coins and q. Remember that coins and q is actually a part of the cholesterol. I mean, it's part of the electron-transport chain, right? So, if you're taking a HMG query, doctors, inhibitor, right? You have ultimately, you have decreased levels of coins and q. If your levels of coins and q go down, think about it. You potentially have decreased ATP synthesis, right?

And if you have decreased ATP synthesis because your electron-transport chain is shot, your sodium potassium ATP is pump will stop working. And if it's not working, right? Sodium will flow down its gradient into cells. If sodium flows down its gradient into cells, water will follow. Your cells can swell and explode. Okay? So, this is potentially the mechanism behind the myotoxicity that people get with statins. Now, another thing is that I said that for you to make VLDL, right? Cholesterol binds with triglycerides, right? To form a cholesterol ester that then forms VLDL along with it will be 100. The thing is, if you inhibit HMG query, doctors, you're not longer making cholesterol and the amount of, the intracellular amount of cholesterol in your hepatocytes go down. Then it's like your triglycerides kind of hang out in the liver, right? And they could potentially cause like fatty liver, okay? So, this is the potential mechanism behind the hepatotoxicity that goes along with statins. So, the big toxicities you want to know, your statins are hepatotoxicity and myotoxicity. Now, the next ones I'll talk about are the fibrates. Okay? Your fibrates, they are P-par alpha activators. Okay? So, think of like P-par, I think, it stands for like peroxysome, proliferator activated receptor alpha. Okay? So, they are P-par alpha activators. Okay? Remember, P-par alpha is actually a transcription factor for LPL, for lipoprotein lipids. So, think about this.

If you activate P-par alpha, you increase in the, you activate in a transcription factor for lipoprotein lipids. If you activate lipoprotein lipids, some, if you make more lipoprotein lipids because you're increasing its transcription, you'll basically clear triglycerides from the serum. This is why fibrates are the best drugs for lowering triglycerides. Now, please, do not confuse P-par alpha with P-par gamma. Okay? Do not confuse P-par alpha with P-par gamma. P-par gamma is what is affected by your TZD, your thiosolidine diodes, which are drugs used for diabetes. Okay? And the classic drugs that you see on exams with the fibrates are like Gen-fibrezile. So, Gen-fibrezile, right? Feno-fibrate, chlorfibrate, phenofibrate, blah, blah, blah. Okay? And these drugs, you don't want to give them with statins because there's an increased risk of myotoxicity. Okay? And let's see, this podcast has gone on for long. So, I don't have the time for that, but these drugs also increase your risk of ghost tombs. That's something I have to know for step one. And don't forget that these drugs also inhibit its cyrochrome P450. Okay? So, again, just so they keep that at the back of your mind. Now, the next drugs I'll talk about are your bylastic binding in resin, right? Your bylastic binding agents, right? So, their drugs like cholesterol,amine, cholesterol, cholesterol, cholesterol, am. I remember a bowel is made from cholesterol, right? And please don't forget, right?

The weekly meeting enzyme in bowel synthesis, a bylastic synthesis is seven alpha hydroxylics. So, bowel is made from cholesterol, right? So, the thing is, if you bind up bowel, your liver is like, oh, crap, why do I not have bowel? So, your liver tries to increase its synthesis of bowel. So, your liver by increasing the synthesis of bowel is increasing the utilization of cholesterol. If you increase the utilization of cholesterol, well, guess what? Your liver is like, oh, no, I don't have enough cholesterol in my hepatocytes. So, by so doing, your liver will also increase the expression of LDL receptors, and now clear more LDL from your serum. Okay? Because again, LDL has cholesterol that the liver can use. So, again, these drugs are good at lowering blood LDL, but they're not as good as statins. Statins are the best drugs for lower NLDL. Okay? But there are a few problems with these drugs, right? Obviously, right? You have a fat soluble vitamin deficiency, right? Because you need bowel to emulsify those fat soluble vitamins like, vitamin A, D, and K, right? So, you're a deck vitamin. And then, don't forget, right? These drugs can cause a diarrhea, right? Because the bowel is sort of hanging in your GI tract, right? So, these people, they can guess the diarrhea. You probably don't want to hang out with these people on a plane ride, right? Because you'll get a new definition, or you have an appreciated understanding of what a farting, like a very good fart smells like. Okay?

Now, one weird unusual thing you may get, and don't forget, please don't forget, I'm just saying this to integrate some pathology here, but don't forget that bile is absorbed in the terminal ileum, just like vitamin B12. Okay? Remember that whole business with entero hepatic recirculation. Okay? Now, one other weird thing with the Bylastic Binding Raisins, especially cholesterol, cholesterol, cholesterol, I mean, is very good at binding C-dif toxin, okay? So, just one of those weird things you want to keep in mind, right? So, you can actually use it as one of the adjuncts to the treatment of a pseudomembronosol colitis. Although pseudomembronos colitis, these days is treated with vancomycin, vancomycin is now the first line agent. No longer metronidousol. Okay? Now, EZMI is the next one. Basically, EZMI prevents the reabsorption of lipids in the GI tract. That's literally all you need to know. And then niacin, no one really knows how niacin works, but how you think you want to know niacin is the best drug at increasing HDL. Now, one of the high you think you want to know with niacin is niacin, right? They're actually receptors that respond to niacin on the surfaces of mice cells. So, if you take niacin, niacin can bind to those receptors of micelles, now cause a de-granulation of those micelles. And they release things like histamine, right, and prostaglandins.

So, remember, histamine and prostaglandins, they cause visual dilation, so that's why you can get flushing with niacin. But another thing that can happen is histamine causes itching, right? So, you can get an itch, like very bad, I'm forgetting the medical term now for itching, but you can itch a lot with niacin. So, the way you can actually prevent this is, you just tell the patient to tough it out, right? After a while, the effects sort of go away, but one thing you can do is you can give, like you can pre-treat the patient with aspirin, right, or cox inhibitor. Because, when inhibiting cox, you don't make prostaglandins, right? And if you don't make prostaglandins, you're basically taking away the stuff that can come from micelles, indigratulation, like prostaglandins, right? Although you still have the histamine, but in general, if you give an inset, a cox inhibitor, that sort of takes care of the itching and the flushing that goes with the niacin. And then, the next drugs I want to talk about, I want to talk about the PCSK-19 inhibitors. Remember, I said that PCSK-9 breaks down LDL receptors inside hepatocytes. So, if you inhibit that PCSK-9, you will stop breaking down LDL receptors. They will persist for a longer time period on the surface of hepatocytes. So, you will increase the clearance of LDL from the circulation. These drugs work extremely well, okay? Only problem is they are very expensive.

But the clear, the big ones you want to know here, they are all ending Q-Map, right? So, like, if a lock-umap, a Lyrocumap, okay? They are all monoclonal antibodies against the PCSK-9 enzyme. Now, one other drug I want to talk about is my poor mercen. This can be an unusual drug you may see on your exam that pretty much everyone will get wrong, but you won't get it wrong because you listen to this podcast. But you can make this into like a cell biology question on step one, right? So, how can they do that? The thing is my poor mercen is actually an anti-sense RNA, okay? Against the mRNA of APOB100, okay? So, basically, it basically clobbers cuts down on your... The amount of APOB100 you have, because you don't make it any more, because you just always kill the mRNA. So, by doing that, you decrease the release of VLDL from hepatocytes. If you decrease the release of VLDL from hepatocytes, well, guess what? You basically will never make LDL. If you know Mika LDL, guess what? Your LDL levels will be low, okay? So, they may make this a genetic experiment question on step one. The thing is this drug super powerful, but it's super expensive, but, classically, it's used to treat like the familial hypercholesterolinias. And I think that's it for these lipid drugs. I guess I'm just saying some quick things about three other drugs here. Methylgene is another drug. It's used more for OB.

No one really knows how it works, but basically it's used to treat postpartum hemorrhage, because it can constrict the urine vessels. Only problem is you don't want to give this to people that have a history of viso-spastic disease. People that have renaultes phenomenon or prince metals angina, also called virant angina, or preclamsia. People believe that it arises from viso-spasim as well. So, you want to avoid methorgying those people. The other drug I want to talk about is necceratide. Necceratide is an analogue of BMP, or brain-naturitic peptide. Remember that BMP actually increases guanilite cyclis activity, right? And it also increases diuresis, right? So it lowers your blood volume, but it also lowers your blood pressure, but it also causes visodilation, right? So these drugs can be used to treat a heart failure, okay? So necceratide is a drug that actually helps with that. It's a BMP analogue. And then the last drug I'll talk about is sacubitril. I do not believe that sacubitril is in first state, but I can almost predict that this drug will make its way to an MBM exam at some point in the not-too-distant future. The thing is how the sacubitril works. So, Cubitril is an epilizing inhibitor. Well, what is neprilizing? Neprilizing is an enzyme that breaks down AMP, that's etro-naturitic peptide, and BMP, brain-type-naturitic peptide. And I already just told you that these MPMP caused visodilation and increased irises.

They actually also blunt the effects of the ring-in-an-gytension of theosterone system, which is amazing, right? So these drugs are good for heart failure, okay? So if you gave an epilizing inhibitor like sacubitril, your levels of AMP and BMP will go up because they no longer have broken down. And you get all those awesome effects, okay? In fact, sacubitril is now combining a drug. If you watch TV, there's this drug known as Intresto. It's like this popular ad where some old guy is saying, like, tomorrow, tomorrow, I love you, tomorrow, right? So it's like Intresto. Intresto is a heart failure drug. And I was actually being shown to have some benefit. But basically, Intresto is a combination of an ACE inhibitor and sacubitril, okay? Works really well for certain subsets of heart failure, especially when you reach certain like New York Heart Association or Classifications. So I think this is where I'm going to stop. And really, this is the end of cardiac pharmacology. So I know these were a long series of podcasts, but if you listen to the three cardiopharm podcasts, you will learn not just the drugs, but you'll learn a lot of cardiac pathologies, a lot of arrhythmia stuff and whatnot. So I wish you all the best. Again, happy Thanksgiving. God bless, and I'll see you in the next podcast. Thank you.

It acts primarily as a venodilator, decreasing preload and thus reducing the heart's workload.

$\text{PDE}3$ inhibitors (e.g., Cilostazol).

Inhibition of HMG-CoA reductase leads to decreased intracellular cholesterol, which triggers upregulation of hepatic LDL receptors.

Fibrates (by activating $\text{PPAR}\alpha$, increasing LPL).

Myotoxicity and Hepatotoxicity.

The patient will not respond to potassium or calcium supplementation because magnesium deficiency impairs ion handling in the kidneys.

$\text{APOE}$, $\text{APOC2}$, L-CAT, and $\text{APOA1}$.

Magnesium Sulfate ($\text{MgSO}_4$). High levels decrease PTH release; low levels increase PTH release.

ACAT (Acyl-CoA cholesterol acyltransferase).

PCSK-9 inhibitors (e.g., evolocumab, alirocumab). They prevent the degradation of LDL receptors, increasing LDL clearance.

$\text{PDE}3$ inhibitors increase cAMP (used for PAD/heart failure); $\text{PDE}5$ inhibitors increase cGMP (used for erectile dysfunction/pulmonary hypertension).

To prevent the constriction of the efferent arteriole caused by Angiotensin II, thereby mitigating hyperfiltration injury.

$\text{APOE}$, $\text{APOC2}$, L-CAT, and $\text{APOA1}$.

Magnesium Sulfate ($\text{MgSO}_4$). High levels decrease PTH release; low levels increase PTH release.

ACAT (Acyl-CoA cholesterol acyltransferase).

PCSK-9 inhibitors (e.g., evolocumab, alirocumab). They prevent the degradation of LDL receptors, increasing LDL clearance.

$\text{PDE}3$ inhibitors increase cAMP (used for PAD/heart failure); $\text{PDE}5$ inhibitors increase cGMP (used for erectile dysfunction/pulmonary hypertension).

To prevent the constriction of the efferent arteriole caused by Angiotensin II, thereby mitigating hyperfiltration injury.