Drugs for dyslipidemia

You are discussing a problem on a patient, uh, in a patient of 16 years old who was diagnosed with familial hypercholesterolemia, homozygous type. And, uh, because of which he had a peripheral arterial disease. So there are two triggers in which you are encountering the names of drugs that are used for treating this patient.

So in the first trigger of number five, there is a mention that this patient was treated with a drug called aspirin. What is aspirin? Have you heard of this before, or this is the first time you're encountering this drug? Any idea?

>> Yes, we did hear about it before.

>> What is that, Iman? What is it used for?

>> It is used for many reasons, like it could be anti-platelets or anti-inflammatory.

>> Anti-inflammatory and anti-platelet. Very good. And in this unit, we are using aspirin at a dose of 81 mg. 81 is considered to be a low dose. At this dose, sorry, at this dose, aspirin acts as an anti-platelet drug, which prevents the aggregation of platelets and thereby reduces the size of thrombus.

Last week, we discussed a class of drugs called anticoagulants. Correct? Heparin, warfarin, directly acting anticoagulants. So we discussed these three last week. They also prevent the formation of thrombi. So what is the difference between aspirin and anticoagulants? What do you think is the difference? Go ahead.

>> One targets the platelet and the other one targets the, uh, coagulation cascade, which is mainly...

>> Very good, excellent. So the aspirin is going to target the platelet aggregation. On the other hand, the anticoagulants that we discussed last week, they're going to target the clotting factor coagulation cascade. That's because if you remember last week's case, it was a 70-year-old gentleman who was, uh, hospitalized, bedridden for 5 days and developed a thrombus in the deep veins of the leg. So it was a venous thrombus. A venous thrombus, if you analyze it under the microscope, you will see that it has clotting factors.

On the other hand, if you take this week's case, Sami, he also complains of pain in the leg. But there is no problem with the veins. The problem is with the arterial blood vessels. The arteries are unable to supply the nutrients necessary for the tissues of the food. That's because they are narrowed down. And here again, there is a thrombus, but it is made up of mainly platelets. So an arterial thrombus, you need to use a drug that can target the platelet aggregation, and that is why aspirin is used at a low dose. The low dose is important because you will encounter this name of the drug once again in unit 7, where its main purpose is being used as an anti-inflammatory drug. So for that purpose, the dose of aspirin is almost, almost close to, you know, 50 times more than what we are using it for its anti-thrombotic effect. So it is the low dose, you need to stress on the low dose aspirin. So this is the first point that you should all be aware of. In fact, I think Ahmed had this question last week. Ahmed or Mohammed had this question last week, and that is nicely emerging out from this week's problem. So that's the first objective. Why is, what is low-dose aspirin and what is its, you know, purpose of using it in our patient?

Second, in another trigger, you will see the names of drugs called atorvastatin, ezetimibe, alirocumab. And this is the first time you're encountering the names of these drugs, and that's why it is important for us to have a discussion on what are all the drugs that are commonly used by an undergrad doctor to control abnormal lipids. You need to be aware of six classes of drugs used for treating dyslipidemia. The first four, which I'm going to tell now, they are particularly used in cases where LDL cholesterol is high, which is one of the most common dyslipidemic states you will see in clinics: high LDL cholesterol. So the drugs are statins, ezetimibe, bile acid sequestrants. So these four, their main target is LDL cholesterol. In fact, in the problem, the first three are used together: statins with ezetimibe with alirocumab. They're used together. Then fibrate derivatives, which is the drug of choice if your main goal is to reduce triglycerides in the patient. And lastly, although not commonly used, you should be aware of a drug which has a lot of serious adverse events called nicotinic acid or niacin. So the first four classes of these drugs target LDL cholesterol.

How do we get cholesterol? What are the sources of cholesterol in our body? So you can get cholesterol either from an exogenous source, where the diet, diet forms the main source, or you can synthesize it in the body. The liver takes the job of synthesizing cholesterol in the body. So the cholesterol is available to our body by both exogenous and endogenous ways. It is always better to have a balance between the amount of cholesterol which is synthesized and which is absorbed from the diet, as well as the amount of cholesterol which is being degraded. As long as there is a balance, it's like a seesaw. As long as you have a balance, there is no problem. But when you have excess synthesis of cholesterol or excess absorption through the diet or reduced degradation, both will increase the LDL cholesterol in the blood, and that gets deposited as atherosclerosis, and that causes peripheral arterial disease that we are seeing this week. We'll be seeing next week, the same atherosclerosis is also the reason for people to land up in coronary artery disease. So it causes a lot of problems when LDL cholesterol gets accumulated. And so we have four classes of drugs that can tackle this excess LDL.

If you have to reduce the LDL cholesterol, you can achieve it either by reducing the amount of cholesterol that is available to the body. So either you can reduce the amount which is endogenously synthesized, or you can reduce the cholesterol which gets absorbed from the diet, or you can enhance the degradation. So by both strategies, you can reduce the LDL cholesterol. So the statins, which are the most commonly used drugs for reducing LDL cholesterol, they act by reducing endogenous synthesis of cholesterol. So there is a key enzyme in the liver called HMG-CoA reductase, and statins act by inhibiting this enzyme, and thereby they reduce the endogenous cholesterol synthesis. And other two drugs, ezetimibe and bile acid sequestrants, they act by reducing the quantity of cholesterol that gets absorbed from the dietary source, and thereby they reduce the exogenous cholesterol absorption. Finally, they will also reduce the LDL cholesterol. PCSK9 inhibitor, in which you have a drug called alirocumab. It facilitates the degradation of cholesterol by increasing the expression of LDL receptor on the liver. So by facilitating the degradation of LDL cholesterol, it also will reduce the quantity that is present in the blood. So this is a bird's-eye view, an overview of how different drugs act by reducing LDL cholesterol. We'll go into the specifics individually.

Let's take the first class of drugs called statins. The first thing you should all be aware of is how do statins act? What is the mechanism by which it acts by reducing LDL cholesterol? So you can go through this video. Just let me know if you can hear the sound. Is the sound clear to you all? Just let me know in the chat.

>> Doctor, you cannot hear.

>> Sorry. Uh, was it Ian or who? Sorry.

>> We are not able to hear it.

>> Yeah, we are not able to hear.

>> Aren't you able to hear that? No. Uh, okay. All right. Maybe I'll send that video as a separate attachment. Uh, maybe it is not showing up. Uh, can you see that? Can you follow that?

>> Yeah, we saw it, but we did not hear.

>> Okay, that's fine. That's fine. Okay. See, the key point that you all should keep in mind is, the liver is like a factory. It has to synthesize cholesterol. It cannot live without synthesizing cholesterol. That's because one of the key functions of the liver that you might have studied in your year one in biology course is, liver is important to synthesize bile acids. Correct? Bile acids, they are largely made up of cholesterol. So for this purpose, liver needs cholesterol, and so it has a pathway by which acetyl-CoA is utilized to finally, through a series of enzymes, cholesterol is synthesized. And one of the enzymes which is the rate-limiting step in cholesterol synthesis is HMG-CoA reductase. So it is like a bottleneck. It is the one that controls the rate at which cholesterol is being synthesized by the liver. When you give statins, any statin, what happens is it goes to the liver, binds to this HMG-CoA reductase, and it inhibits its function. Once the enzyme is inhibited, in the liver, hepatocytes, liver cells, cannot synthesize cholesterol. Liver cannot synthesize cholesterol, but it has to have it, only then bile acids can be synthesized. So what will the liver do? It will look for alternate sources of cholesterol. So it will look in the body, where does, where is cholesterol present? Is it located elsewhere so that it can borrow it? It can take it from that site. By doing so, liver identifies that in the blood, there are a lot of LDL cholesterol which are rich in cholesterol. So the lipoprotein LDL is rich in cholesterol. It identifies that, and so to use the cholesterol from LDL, on its surface, it starts overexpressing LDL receptors. So by inhibiting HMG-CoA reductase, finally, what you will observe is the overexpression of LDL receptors on the surface of liver cells. And what do LDL receptors do? They bind to the circulating LDL cholesterol and they scavenge them. LDL cholesterol will be internalized into the hepatocytes, liver cells, and it will be broken down, and that cholesterol will be utilized by the liver for its normal function of producing bile acids. So by doing so, what happens to the circulating LDL cholesterol? It reduces in the blood. That is what you wanted in Sami, right, our patient? That is what you will be wanting it in patients who have high LDL cholesterol, circulating LDL cholesterol. So you will achieve it by inhibiting the HMG-CoA reductase enzyme. So this is what that video was, you know, demonstrating you. Is that clear? The mechanism of action of statins is that clear? Because this is important. Only then you will understand how do other drug classes also act in tandem with statins. Is that clear? Any doubts?

>> Is it clear, doctor?

>> All right. Thank you. Other than reducing the lipids, LDL cholesterol, statins also have independent effects which are called as pleiotropic effects. They are not related to the LDL cholesterol synthesis inhibition. They are independent, unrelated. But if you put all these together, they are very protective in patients who are at risk of cardiovascular disease. For example, any statin that you take can reduce platelet aggregation. Of course, it won't be reducing the aggregation of platelets like aspirin, like low-dose aspirin, as a much more potent inhibition on platelet aggregation. So you cannot compare it with a drug whose sole purpose is to inhibit platelet aggregation, but to a limited extent, even statins can inhibit the aggregation of platelets. It's a good positive effect. It's an advantage. Second, they possess antioxidant properties. They reduce the rate at which atherosclerotic... I think some noise is heard. Um, yeah, just mute yourself. Yeah, I don't know who is that. Just mute yourself. Okay. All right. It possesses anti-atherosclerotic property. It will reduce the rate at which the lipids in the atherosclerotic plaque gets oxidized. It will reduce the rate at which the atherosclerotic plaque expands. It will increase the thickness of the fibrous cap, thereby it reduces the chances of atherosclerotic plaque rupture. So all these are beneficial effects of statins which are not related to their hypolipidemic effect. These are called as pleiotropic effects of statins. Be aware of this excellent effect which will work together with hypolipidemic property, and that is how clinically it is far better than, you know, any other class of drugs that can reduce LDL cholesterol. Of all the types of lipoproteins, the maximum effect of statins you will see it with LDL. LDL reduces to an extent of nearly 20 to 55 percentage. You will also see a reduction in triglycerides, but not great, maybe 10 to 30 percentage. Similarly, HDL might also increase, again, a minimum 5 to 15 percentage. Okay, not great, but the greatest effect will you will see in the reduction of LDL cholesterol.

There are half a dozen statins that are used clinically, and any drug in this class will end with the suffix "statin." So if you see a drug ending with "statin," it means it belongs to the statin class of drugs which inhibit HMG-CoA reductase, whose main effect is to reduce LDL cholesterol. These three names you can keep in mind, very commonly used in clinical practice: atorvastatin, rosuvastatin, simvastatin. Just keep these three names. And if you see a drug ending with "statin," associate that drug to this class of agents.

When you are giving it to patients, you should be aware of the time at which you are supposed to prescribe statins. Understand, statins act by inhibiting cholesterol synthesis in the liver, and any biological parameter that you take, any biological phenomenon that you take, blood pressure, blood sugar, you know, um, any parameter, okay, you take will not stay static throughout 24 hours. They undergo cyclic variation, which is called as circadian rhythm. So even cholesterol synthesis, it is not the same throughout 24 hours. At some time of the day, it will be low. At some time of the day, it will be at its peak. Particularly for cholesterol synthesis, as you can see here, the peak synthesis occurs in the evening, and at night it will, and at other times of the day, it will be very less. So if you have to inhibit cholesterol synthesis, your statin class of drugs should mainly be available at night. Only then you can have maximum inhibition. So that is why whenever statins are prescribed in clinical practice, you will see they are most often prescribed to be taken at bedtime. However, atorvastatin, rosuvastatin, these two are quite long-acting. So even if a patient takes it in the morning or in the afternoon, these two drugs will still be at their peak when cholesterol synthesis is at its peak at midnight, and you will see their effect on inhibiting cholesterol synthesis. So that's why atorvastatin, rosuvastatin, it doesn't matter, any time of the day it can be taken. If statins other than these are prescribed, it is always better to take it at bedtime so that their maximum concentration in the blood will overlap with the peak of cholesterol synthesis, and you will achieve the maximum therapeutic effect. So this is one clinical point that you all should keep in mind. Okay. The time at which statins are being prescribed.

Just a question. How is warfarin prescribed? At what time should warfarin be taken by a patient? If you can recollect from the previous session, anytime is fine. What? I think so.

>> Okay. Okay. All right. Just go back to the presentation and probably in the next session, you can, you know, share your, uh, thoughts. Okay.

A drawback of statins is it is metabolized by the liver, and that too by enzymes which are commonly involved in the metabolism of many other drugs. So that's why statins exhibit a wide range of drug interactions. You have some of these statins which will inhibit the drug-metabolizing enzymes in the liver. And so when you're going to concomitantly add a drug in a patient who is receiving a background statin therapy, you have to make sure it doesn't interfere with the metabolism of statin. So drug interactions, this is also a common feature. Like warfarin, warfarin also exhibits a wide range of interactions with other drugs. Statins do exhibit the same.

Okay, Sami, before you started him on statin, did you do any lab investigation? Did you perform any lab investigation in our patient?

>> Yes.

>> What did you do, Iman?

>> They checked the lipid profile of the patient.

>> Very good. Why?

>> To know which drug to prescribe, and then this will aid them in the diagnosis.

>> Okay. Okay. Uh, see, for LDL, the Sami had excess LDL cholesterol, right? So for LDL cholesterol, you have statins, ezetimibe, bile acids, and alirocumab. That's it. No other, you know, this is only choice for you. And statins are always the first and the best. Okay. So you're going to start him on statins. But statins are hepatotoxic. They cause liver damage. So having started a patient on statin, and the patient comes back to you with jaundice, this with, you know, yellowish discoloration of skin, clear and urine, sometimes they can also land up in fulminant hepatic failure. So to, and this risk is high if before statins, they have some serious liver problems. So to make sure Sami doesn't have any liver problems, and to have a baseline level of liver enzymes, so that you can, if any changes happen post-therapy, post-statins, you can, you know, clearly associate that abnormal liver function to statin therapy, you have done, always you have, you have, you have, you know, um, um, carried out liver function test at baseline. So that is a must. Guidelines do recommend before you start a patient on statin, check the liver function test, and if it is normal or mild derangement, doesn't matter, start them on statins.

Another adverse effect, other than hepatotoxicity, that you should all be aware to monitor in a patient receiving statins is rhabdomyolysis. It is a life-threatening serious adverse event that can lead to renal shutdown, renal failure, and patients can die. So any patient who is going to complain after starting statins with severe muscle pain, the patient complains, myalgia is very common. Whosoever is taking statins, if you ask them, do you have any complaint? They'll say, yeah, I'm having a low back ache, it's hurting on my, you know, shoulder. So myalgia is an extremely common complaint that you will see in all patients. But if they say severe pain, muscle pain, you need to make sure they do not have rhabdomyolysis. So the patient has to be immediately taken to the hospital, and you can order for creatine phosphokinase, a liver enzyme that can, if it's elevated, that will indicate rhabdomyolysis. Go ahead, Iman. Go ahead. You have a question.

>> Yeah, doctor, what is the reason for this rhabdomyolysis?

>> Ah, good, excellent question. There are a lot of, you know, uh, hypotheses. Particularly the statins, when they are, uh, uh, they're metabolized by that various enzymes, right? CYP3A4, CYP2C9. So patients who have polymorphisms in these enzymes, they inadequately metabolize statins. So statin active concentration will build up in the blood, and that goes to the muscles and causes rhabdomyolysis. Most commonly, these polymorphisms of the metabolizing enzymes, 3A4, 2C9, and there is a downstream enzyme called UGGT, which is... See, drugs are metabolized in the liver in two phases: phase one and phase two. Phase two is by conjugation reaction. You will see them in unit five. And polymorphisms in these enzymes are the ones which have been most commonly observed to increase the concentration of statins in the blood, which goes and directly causes this muscle-related toxicity. This is one of the very common. Second common reason that you all should be also aware, which I will be talking about in a while, is, see, many times patients do not have only LDL cholesterol elevated. They may also have, in addition, triglycerides elevated. And if a patient has both hypertriglyceridemia and LDL cholesterol very high, for LDL cholesterol, you will be using statins. And for controlling triglycerides, you may have to use fibrate class of drugs. When you combine fibrates and statins, again, fibrates will interact with statins. They inhibit the enzyme which is used for metabolism of statin. Statin level builds up in the blood, and that again increases the risk of rhabdomyolysis and myopathy. So it's basically the enzyme interaction, either by polymorphism or by concomitant drugs, which will precipitate rhabdomyolysis. It is preventable, and you need to be monitoring the patient and do not take it, you know, as a trivial issue when patients complain of muscle pain, particularly severe muscle pain. It could be the earliest sign of rhabdomyolysis. So you can identify, stop statin therapy, give them hydration, and, you know, intense monitoring, you can recover them, you can prevent acute renal failure. Okay, that's an excellent question, Iman. Any other questions before we move to the next class?

Okay. So the next class of drug is ezetimibe. What happens in patients who are being prescribed statins is, let's say you are prescribing statin to Sami today. Today is what? Today is, uh, 21st of April. Correct? So let's say you are starting him on statin, and considering his familial hypercholesterolemia, probably you will give statin at its maximum dose. Okay. What happens after a month or after two months or after three months or after six months down the line is, Sami will be taking statin. Let's assume you are prescribing him only statin as monotherapy. So the target of statin is HMG-CoA reductase. So the enzyme will be inhibited in the liver. Liver will overexpress LDL receptors so that it can remove the LDL cholesterol from the blood. But after several weeks to months, what is likely to happen to the intestinal absorption of cholesterol as a compensatory mechanism? Because you have now inhibited endogenous synthesis, the body will now try to compensate it by increasing the expression of transporters on the intestine through which cholesterol from diet, they get absorbed. So after a few months of use of statins, the body will try to develop some sort of tolerance. Why? Because more cholesterol is getting absorbed from diet, and liver will start using that cholesterol. So no more it will start using LDL cholesterol that is circulating in the blood. So the circulating LDL cholesterol will shoot up. So this develops some sort of statin tolerance. So those patients who have initially responded to statin therapy well, but after a few months, if they fail to show a consistent reduction in LDL cholesterol, they should be prescribed a drug called ezetimibe. So this ezetimibe is an inhibitor of intestinal cholesterol transport protein. So it inhibits intestinal absorption of cholesterol. So liver will not have any choice. So if you give him, if you give that patient a combination of statins and ezetimibe, the liver in that patient will have no choice other than taking only LDL cholesterol from blood. We don't start everyone on this combination because mostly they will respond very well to statin therapy. If at all they develop tolerance, then you can consider adding ezetimibe to statin.

The third drug which interferes again with LDL cholesterol which was used in our patient is PCSK9 inhibitor, a drug called alirocumab. What is PCSK9? PCSK9 is a protein which is involved in degrading LDL receptor. It facilitates the endocytosis of LDL receptor. It facilitates the degradation of LDL receptor. So if LDL receptors are not available on the hepatocytes, LDL cholesterol cannot be scavenged. So PCSK9 inhibitor acts by inhibiting this PCSK9 protein. Thereby more LDL receptors are expressed on the surface, and so more LDL cholesterol is scavenged. Only catch here is it's a monoclonal antibody. How do you give any monoclonal antibody? You must have seen in unit two, a drug for RSV, respiratory syncytial virus, any monoclonal antibody, what is the root of administration? It's an antibody. So what do you think, as like statins and ezetimibe, you think it can be given orally?

>> Iman.

>> Uh, doctor, we've answered in the chat box.

>> Sorry.

>> Um, we've answered in the chat box.

>> IV and sub...

>> Oh, is there? Oh, okay. Okay. Okay. I'm sorry. I think the chat, you have to refresh every time. It looks like. Okay, just now I'm seeing. I'm sorry. Okay. Just now.

>> Injection.

>> Oh, very good. Okay. Good. Well done. So any antibodies, they are made up of peptides. If they are made up of peptides, if they are made up of amino acids, you cannot give them. So it has to always be parenteral. Parenteral. Okay. It can be an injection, or you can directly inject it in the site where the problem is. So it has to be always outside the GI tract. So because of this reason, you don't give alirocumab to patients who develop this dyslipidemia in 40 years or 50 years of age. You use it only to patients who have severe dyslipidemia, who has no other choice other than, you know, this injection. So that's why Sami, who was diagnosed with homozygous familial hypercholesterolemia, which is the worst case that you can expect the dyslipidemia to happen, is administered alirocumab. Otherwise, you will not see this being used in a patient who is 40 years old or a 50-year-old who has coronary artery disease, who has atherosclerotic cardiovascular disease, you will not see them using alirocumab. For them, statins are enough. If statins are, you know, inadequate, a combination of statins with ezetimibe will do the job perfectly. Okay. If you compare the effect of LDL reduction with these three classes of drugs, PCSK9 inhibitor is the best in the class, but it comes with a disadvantage that it has to be always parentally injected. So because of which, we don't use it that commonly, except for patients with familial hypercholesterolemia. Then comes statins. Statins, in fact, the best amongst the drugs that will tackle LDL cholesterol. Best in the sense, both its ability to reduce LDL cholesterol as well as its side effect profile compared to other drugs. Statins, much, you know, have a much better safety profile. And ezetimibe, you always use it only in combination with statins because its LDL cholesterol reduction, you know, ability is very low. So that completes these three classes of drugs which are put in our patient's arm.

The fourth class of drug which can also reduce LDL cholesterol, but we use it selectively only in certain subpopulations, is bile acid sequestrants. Some textbooks also say it as bile acid resins. Both are synonymous. Bile acids. The unique feature of bile acids is, you must have read it in biology. It is synthesized by the liver. Liver releases bile acids through the bile duct to the intestine, and in the intestine, it is important for absorption of fats, fat-soluble vitamins. Once those get absorbed, beauty of bile acid is, 95% gets reabsorbed through circulation through a mechanism called enterohepatic circulation. So if liver synthesizes 100 molecules of bile acid, for the first time, it will release them through the bile duct, that will go into the intestine, facilitate the absorption of fats and fat-soluble vitamins, and 95 molecules will come back to the liver. Only five molecules will get excreted. So every time, for the first time, a liver synthesizes 100 molecules, it does the job. 95 return. It returns back. So next time, the liver has to synthesize only five more molecules of bile acid. But now what happens when you use this class of drugs, bile acid sequestrants? They are taken orally, and when they reach the intestine, they bind to this bile acids which are released through the bile duct. They will not allow this enterohepatic circulation to take place. So now the bile acids will, if 100, liver releases 100 molecules of bile acid, a patient who takes bile acid sequestrant, all these 100 molecules will bind in the intestine and they get eliminated and they get eliminated, excreted in the feces. Excreted, I'm sorry, there is excreted in the feces. So every time the liver has to freshly synthesize 100 molecules of bile acids. And bile acids, the main component of them is cholesterol. So where does the liver get cholesterol from? It knows blood has a lot of LDL. So it increases the expression of LDL receptors, through which LDL cholesterols are scavenged, and that cholesterol is used for producing more bile acids. So that is how bile acid sequestrants also act, and they reduce the LDL cholesterol. These are the names of three bile acid sequestrants that are used in clinical practice: cholestyramine, colestipol, and colesevelam. And as you can see, they always have "chol" or "col." Okay, that gives you an indication that these are all bile acid sequestrants. Do bile acid sequestrants get absorbed? The answer is no. But if you take statin, it gets absorbed, right? If you take alirocumab, it gets absorbed. And that is why in patients, particularly in a pregnant woman, if she has high LDL cholesterol, then you need to use a drug which will not cross, which will not get absorbed, and which will not cross the placenta. And so bile acid sequestrants are preferred. Why are we not using in other patients? That's because the first thing, their effect on LDL cholesterol, absolute effect on LDL cholesterol, is relatively low compared to statins. And second, they are associated with a lot of abdominal side effects because they prevent the absorption of fats. So they cause flatulence, they cause, you know, long-term intake might lead to deficiency of fat-soluble vitamins. And because they bind to the agent in the intestine, if any other concomitant drug is taken along with bile acid sequestrant, those drugs also will be bound, and their absorption will be interfered. So it encounters a lot of drug interaction. So that's why basically we don't use them in patients other than pregnancy. Even in children, in today's world, we can safely use statins. If statins are causing a lot of myopathy in children or hepatotoxicity in children, in that child, probably you can consider bile acid sequestrants as an alternative. Otherwise, pregnancy is the only key indication for bile acid sequestrants.

The second last class of drug that can be that is used for treating dyslipidemia is fibrate derivatives, where you have the drugs fenofibrate and gemfibrozil. So these two drugs, their main target is an enzyme in the blood vessel called lipoprotein lipase. They activate that enzyme, thereby the triglycerides in the blood will reduce. In fact, of all the drugs that we take, that we can use for dyslipidemia, fibrate derivatives are the best for hypertriglyceridemia. They share two things in common with statins. First, adverse effect profile. As like statins, they are also hepatotoxic. They also cause rhabdomyolysis. So if you have a patient who has combined dyslipidemia, LDL increase, triglycerides also increase, so statins, you can prefer any statin. But amongst the triglycerides, amongst the fibrates which you are going to use it for reducing triglycerides, the safest is fenofibrate. You should not use gemfibrozil when taking statins because the risk of rhabdomyolysis is the highest. People will certainly go up, you know, will develop renal failure secondary to rhabdomyolysis that is precipitated by interaction between gemfibrozil and statin. So if you're going to combine a fibrate derivative, always choose fenofibrate, the safest to be combined with statin.

The last class of drug which you can just be aware of, because you're not going to see them in clinical practice, yeah, hardly it is used, and it is used only by the specialists, is nicotinic acid or niacin. In fact, of all the drugs that we use for treating dyslipidemia, nicotinic acid or niacin is the best. They have the best ability to increase HDL cholesterol. No other drug increases HDL cholesterol like niacin. It is almost like 35 to 40% increase you will see with HDL cholesterol with niacin. But the problem with niacin is, it has got a lot, it causes a lot of serious adverse effects. It damages the liver. It causes hypersensitivity reactions. It can precipitate diabetes, gout, and Stevens-Johnson syndrome, uh, you know, toxic epidermal necrolysis. These are all like life-threatening adverse events because of which patients die. So because of this risk, niacin is no more used as a first-line drug, and you don't have to know in detail about niacin or nicotinic acid.

So to summarize, dyslipidemia drugs for dyslipidemia, you're going to mainly focus on drugs used for treating high LDL cholesterol. The best, most tolerated, most often first-line is statin. If after starting statin, patients are adequately getting controlled initially, but after a few months, if they are not getting, if the LDL cholesterol shoots up, you can try a combination of ezetimibe with statins. Patients who have familial hypercholesterolemia, they need to be given aggressive therapy to reduce LDL cholesterol. So they will need combination therapy: so statins with ezetimibe with PCSK9 inhibitor alirocumab. If you have to control LDL cholesterol in a pregnant woman, you may use bile acid sequestrants. They are not safe. You can't use it in pregnancy. So alternatively, bile acid sequestrants can be a bridge during that nine months window, gestational period. If in addition to LDL cholesterol, you want to also tackle triglycerides, combined fibrate derivative. And if statin and fibrate derivatives are given together, amongst the fibrate derivatives, do not choose gemfibrozil, but prefer fenofibrate. Nicotinic acid or niacin is the best when it comes to HDL increase, but due to its severe adverse effect profile, we do not use it that commonly in clinical practice. Any questions? Any clarifications before I throw you some true or false questions? Go ahead, Muhammad. Go ahead.

>> Uh, yes, doctor. I have a question regarding regarding bile acid sequestrants. So, uh, in bile acid sequestrants, it will inhibit the absorption of, uh, uh, cholesterol in the intestines. Is it right?

>> Correct. It will not... Okay. Okay. Go ahead. Go ahead. Go ahead, Muhammad. Complete your question.

>> So what about the endogenous cholesterol?

>> Very good. Excellent question, Babai. Okay. Just I have to paraphrase my answer. The bile acid sequestrants will not bind to cholesterol in the GI tract. Rather, it directly binds to the bile acids which are released, okay, by the liver. Now, Muhammad, if you recollect, bile acids undergo extensive enterohepatic circulation, 95%. Okay. So that's why every time, liver has to just synthesize 5% more molecules. 95 will come back to it. Now, if you use the sequestrant, it will bind to the bile acids in the intestine. It will not allow this enterohepatic circulation to occur. There won't be any bile acids left from the intestine to go back to the liver. So now, liver, what should it do? It should synthesize more cholesterol. Correct? And if it has to increase the endogenous synthesis of cholesterol, Muhammad, what is the source? It will increase the expression of LDL receptors, and through that receptor, the LDL cholesterol from the blood, they will be taken up, they'll be broken down, and that cholesterol will be utilized for making more bile acids. So the endogenous synthesis will increase, and that will be utilized as a bile acid and it will be excreted in the feces because there is a sequestrant. Got it, Muhammad?

>> Yeah. Yeah.

>> Very good. Excellent. Any other questions? Go ahead. Go ahead.

>> Uh, doctor, regarding the sequestrants, can we say that they have a bit of an anticoagulant effect because they reduce the absorption of fat, so vitamin K will not be absorbed?

>> Ah, that's a good point. Yeah, that's a good point. Uh, only thing, Iman, it happens on a long-term therapy. It doesn't happen like immediately, on a long term, and not in everyone. You cannot, you, you won't see fat-soluble vitamin deficiency in everyone who is taking a bile acid sequestrant. Okay. It happens like, like an adverse event in one or two. So you can't depend on its inhibition on vitamin K absorption for an anticoagulant purpose. You cannot use it for that purpose. But it might interfere. And many times, what happens is, people know that those who are taking bile acid sequestrants are likely to develop fat-soluble vitamin deficiency. So upfrontly, along with bile acid sequestrant, they give a supplement. They give vitamin A as a supplement, so that, you know, the individual landing up in fat-soluble vitamin deficiency is reduced. But I think the guidelines do not support this because not everyone will develop. And, you know, the dietary behavior also varies, isn't it? So you may be, you know, vegetarian, I may be a non-vegetarian. So if you are a vegetarian, you take a lot of green salads and all. So your quantity of fat-soluble vitamin, vitamin K, that goes into your gut will be different from meat. So there are a lot of variations, I Iman, due to which we cannot truly say that it exhibits anticoagulant effect, but it interferes with the absorption of fat-soluble vitamins. I'll put a full stop there. I hope you got it right.

>> Yes, I got it. Thank you.

>> Okay, good. Good question. Uh, Muhammad, go ahead. Uh, my question is about statins. So statins will inhibit the HMG-CoA reductase. Uh, so we have some internal regulation in the liver, especially the genetic regulation like SREBP. So if the enzyme is inhibited, is that will lead to increased transcription of, uh, that the precursor?

>> Correct.

>> Increase transcription of LDL receptor coding gene. Correct. You are referring to that LDL receptor coding gene. Uh, you, what you said is correct. There will be an alteration in the transcription factors. So more genes that code for LDL will be overexpressed, that will increase the mRNA expression of LDL receptors, which will translate into increased production of LDL receptors, and they get expressed on the surface of hepatocytes, and they will scavenge LDL cholesterol. You're right. That's how HMG-CoA reductase inhibition will, you know, channelize the expression of LDL receptor on the liver surface. Correct. Very good.

>> Uh, doctor, also the HMG-CoA reductase itself, uh, it will be increased, the transcription of, uh, that enzyme, other than the LDL receptors.

>> Ah, uh, logically, Muhammad, you are right because you have an external agent now, statins, which is inhibiting that enzyme. Correct? So as a feedback, liver will try to increase the production of enzyme and will try to overcome the inhibition effect by statins. You're right. So as a, as a feedback, the transcription factors that are related to HMG-CoA reductase also will be overexpressed. But then you have a statin which can inhibit that enzyme, and so ultimately cholesterol won't be synthesized. Very good. So this is another point. I think I can relate it to a patient. Let's say who has been taking statins, okay, for several years, and suddenly the patient stopped taking it on a fine morning. Let's assume the patient became non-compliant for whatever reason. Okay. Uh, patient developed myopathy, patient lost, you know, uh, uh, interest, or patient could not afford for whatever reason, patients stopped buying statins. Now, Muhammad, I think you have a lot of HMG-CoA reductase in the liver because statins have been inhibiting it. So the liver has increased the expression. Now it will be like a vengeance. The cholesterol synthesis will happen like a vengeance. Okay? It is like a beta-blocker. You should never ever abruptly stop beta-blocker. Do you remember? Otherwise, it will cause acute...

>> Tachycardia.

>> Tachycardia, more than tachycardia, arrhythmia. And if a patient has a coronary artery disease, it can precipitate acute infarction, and patients can die. Okay. Acute heart failure, and patients can die. So to that extent, it would go, uh, for, you know, cholesterol synthesis. Okay. Very good. That's a good point. I never thought about it. Yeah. Good. Any additional points? Any questions?

Okay. So do we have, uh, other faculty members with us? No. Right. Okay. So in that case, I will just, I have like a few true or false questions. I can engage you with. Just answer me in the text box, chat box. Okay.

Statins primarily lower LDL cholesterol by inhibiting HMG-CoA reductase. What do you think?

>> Well done. Well done. Good.

Gemfibrozil is the safest fibrate to combine with statin.

>> Okay. Good. Good. So what is the safest fibrate that can be combined with statin? Name?

>> Very good. Very good. Fenofibrate. Okay. Keep that in mind.

Niacin is the first-line drug for increasing HDL cholesterol. What do you guys think about it?

>> Okay. So if you see a patient with reduced HDL, you would go for prescribing niacin. That's what the statement means. First-line means if you see a patient who has low HDL, you will prescribe niacin. Okay. Good. So what do we do then? It's not used anymore. What do we do then? If you see a patient who has low HDL cholesterol, what is the option you have for such individual? You can unmute and share your thoughts. What option do we have? If you don't want to use niacin, what is the option for me who has reduced HDL?

>> Sorry, I can't see your hands. Yeah, go ahead. Who is this?

>> Uh, Iman.

>> Iman, go ahead. Iman. Because I opened the chat box, I can't see. Yeah, go ahead, Iman.

>> Maybe advise him to take, uh, HDL, uh, rich foods, for example, diet modification.

>> Very good. Very good. Which is the best non-pharmacological measure for increasing HDL cholesterol? Omega-3? Diet?

>> Exercise.

>> Exercise. Exercise has been shown to be the best method, non-pharmacological measure for increasing HDL cholesterol. It is difficult to be compliant to do it consistently, but that is the best. So you would encourage patients to, you know, um, uh, increase the physical activity. The second point that you should keep in mind is, if a patient has just isolated low HDL cholesterol. Okay. Isolated, meaning his LDL is normal, triglycerides normal. Only the HDL cholesterol is low. You don't have to be aggressively using any treatment. It is not like increased LDL cholesterol where patients have a high risk of coronary artery disease or peripheral arterial disease. Low HDL, isolated low HDL does not have any significant clinical risk. So you don't have to aggressively treat with any drug. Encourage non-pharmacological measures, as you rightly said, increase the dietary source, or you can encourage exercise. Exercise is the best for improving HDL cholesterol.

I didn't discuss with you because I have this item, so I didn't discuss with you during the session. A patient on statin can safely drink a large glass of grapefruit juice without affecting drug levels. What do you think? Grapefruit juice.

>> Okay. Where did we see this grapefruit juice before? Any previous drug class? Did we see this grapefruit juice?

>> Okay. Okay. Good. Very good. Very good. Very good. Uh, Amina, you are right partly, and Iman is also right. Okay. So, calcium channel blockers is where we saw it explicitly, right? So those who are taking dihydropyridine calcium channel blockers, their intra-enzyme will be inhibited if they take grapefruit juice, and they land up in hypotension. Warfarin is also right. Warfarin is also metabolized by these enzymes. Grapefruit juice should not be consumed. Same goes with, or any statins, again, grapefruit juice, you should not, you should explicitly tell them to avoid any fruit juice. Don't say grapefruit juice. They may not be aware of grapefruit, right? And old people, you know, for them, someone else will give the juice, right? So it's better to inform them, don't take any juice. So that will prevent this problem of food-drug interaction. Okay, good.

If a patient develops muscle pain on a statin, the only option is to stop all statins permanently. What do you think? You have a patient who develops, okay, muscle pain. Will you go in stopping the statin which the patient is receiving?

>> Okay. Okay.

>> Why do you think it's wrong, Muhammad? Then what options do you have for that patient who develops muscle pain? What other strategies could you think of?

>> Iman says true, but Muhammad says false.

>> Start monitoring. Okay. Okay. Good. Uh, Iman, it doesn't have to be, you need to stop altogether administering statin. You need to do that if the patient develops rhabdomyolysis. But any patient who is going to develop muscle pain will not have rhabdomyolysis. Okay. You will do a test called creatine phosphokinase, and that will, if it is elevated, that will indicate rhabdomyolysis. But most often, they will not have. It will be within normal, and myopathy, myalgia is extremely common. All who are taking statins will complain. If you have any parent or if you have a grandparent who is taking statins, ask them what are the problems you are having. They will say low back ache, this pain, muscle pain, they feel tired all the time. So this is a common complaint with statins. So you don't have to stop altogether. You can reduce the dose of statins. If let's say they are taking 10 mg, you can reduce to 5 mg. If they are taking 20 mg of atorvastatin, reduce to 10 mg. So dose reduction is one, um, you know, way of reducing it. Second, this is a strategy which we don't follow with many drugs. In fact, I couldn't recollect with any other drug where this strategy is followed, only with statins I could recollect the strategy where instead of giving the drug every day, you give the drug on alternate days. So Monday, Wednesday, Friday, Tuesday, Thursday, Saturday. So something like alternate days, the patients can take. That has also been shown to have reduced risk of myopathy. And patients who have developed myopathy or complaining of myalgia, changing from everyday to alternate days has been shown to reduce this complaint. Ultimately, the studies have shown that be it every day or be it on alternate days, their effect on cholesterol, LDL cholesterol reducing activity is the same. So that is why alternate days is also an option. Okay. So you don't have to stop it. You can consider reducing the dose, or you can give it alternate days. Direct. Good.

What do you think on this case? You have a 75-year-old patient who has heart failure, but his LDL level is normal. So he is asking you, my LDL cholesterol is normal. So why are you prescribing me statins, doctor? What would be your answer to this gentleman? Why did you start him on statins? His LDL is normal. You can unmute yourself, or you can put it in the chat box. Whatever your thoughts are.

>> Go ahead, Muhammad. Uh, maybe because, uh, in heart failure, we have some issue in, uh, you know, uh, getting the blood into the vital organs. So the blood that will go to the liver will be reduced, and that will lead to dysfunction of the liver.

>> Ah, okay. I got...

It Muhammad. So you are trying to say a patient with congestive heart failure, a right-sided heart failure, right? And because of the backflow logging uh there is likely to be enlargement of the liver and so something can happen to cholesterol synthesis. Correct? Is that what you're postulating mo?

>> Uh yes.

>> Okay. Good. A good thought. Very good. Very good thought. But yes, I >> maybe to avoid fure uh future um cardiovascular diseases >> uh such as >> like aosclerosis.

>> Okay. Okay. Good. And startins do they have any additional effect other than reducing LDL cholesterol? You remember pleotropic?

>> Yes.

>> They are um preventing the clotting.

>> Very good. Very good. So they have a lot of pleotropic effects. They prevent clotting. They reduce the oxidization of aosclerotic block. They make the block uh you know fibrous cap thick so that the chances of rupturing is reduced and they also in the mioardium they also facilitate the conduction of signals through the gap junctions and they reduce this cardiac remodeling. So because of all this pleotropic effect even in patients who have a cardiovascular disease such as MI, anggina, coronary artery disease uh you know and if their LDL cholesterol is normal you can put them on statins and they will benefit by the pleotropic effect of startings. Okay so that's the answer. I think uh we have Dr. Aisha with us. Uh maybe you have any questions to questions in anatomy. Anyone has any questions in anatomy regarding the arteries of the lower limb. Go ahead Ali. Go ahead.

Yes, >> regarding the uh anatomy problem six u how does the after continuous of the fummeral artery it leads to the posterior side and it goes from the medial side to the posterior side of the poplial or

>> yes from uh see the the femoral artery the course of the femoral artery I told you that it is a continuation of external iliac right so after passing behind the inguinal ligament it goes in the femoral triangle when it reaches this area we start calling the artery we don't call it the external iliac now we call it the femoral artery and then this femoral artery will enter a tunnel I mean a uh uh canal which is uh having a membrane roof. You will read you will do the details of that adductor canal in muscularkeeletal unit. For now you just have to know the name. So it passes through the adductor canal which is in the antromedial aspect of the thigh. Okay. Then this adductor canal from the adductor canal it is bounded by adductor muscle. So there is one muscle which is known as the adductor magnus muscle. So this femoral artery will pass through an opening in that adductor magnus muscle and from the antromemedial side it goes to the posterior aspect of the thigh and it continues down the posterior aspect I mean from the adductor canal it reaches the posterior aspect of the thigh it will continue now in the poplitial fossa which is the posterior aspect of the knee joint when it reaches the poplitial fossa you call it the poplitial artery Okay, here in the demo videos, I think in the demo videos it has uh demonstrated. Please uh see the demo videos so that you can understand more clearly where the adductor magnus is and uh how there is an opening in the adductor magnus. So the adductor magnus muscle is a muscle which uh is in the medial compartment and in the posterior compartment of the thigh. So it covers the medial posterial aspect of the thigh. There is an opening there in that muscle which is known as the adductor hiatus. So the femeral artery from the anteromedial side in the adductor canal it goes to the posterior aspect of the thigh through this adductor hiatus. Okay. And then it will become the post in the poplial fossa the region behind the knee joint it is now called the poplitial artery. Okay. Clear.

>> Uh as we classified uh veins between deep and superficial is the there is a classification for arteries or we don't have to know it

>> for the arteries. The arteries are deep structures. Okay. Though you don't have superficial arteries and deep arteries. Arteries are deep structures only. Only the veins will have superficial veins and deep veins. Arteries are they are surrounded by the deep I mean arteries are accompanied by the deep veins. I have a question. Artery cannot be superficial. Artery is carrying oxygenated blood. So it has to be protected. It is protected well protected surrounded by muscles under the deep fasia. Okay.

>> So you don't have you have branches you have cutaneous branches from the arteries which will supply to the skin and all. You have cutaneous branches but the artery main artery itself will be a deep structure deep to the deep fia.

>> I have a question regarding uh problem five uh veins.

>> Huh?

>> Uh can I ask or later on

>> what

>> I have a question Ali if you don't mind maybe we'll discuss the questions related to this week's problem and after we complete the review session maybe you can Dr. Aisha if you can say maybe he has a question related to the previous problem so maybe you can sort it out.

>> Okay. Okay. Okay. And please if you it will be better if you type your question because I'm having some difficulty in hearing your question properly. So maybe I will not I mean maybe you will not be satisfied with the answer which I'm giving because I'm not able to hear you properly. So if you type the question I'll answer your uh question.

>> Okay. I will ask the question. type the question.

>> Good afternoon. Uh Kanan and Dr. Aisha.

>> Hi.

>> I think Iman has a question. She was raising.

>> So let us see. Yes, I'm here also. If you have any question in pathology, Iman

>> I typed my question in the last room.

>> Yes,

>> it is not there. I now we received it. Now we received it. Maybe the connection is slow.

>> Yeah.

>> Uh the femoral vein does it pass through the adductor hiatus? No. The femoral vein doesn't pass through the adductor hiatus. Only the femoral artery will pass through the adductor hiatus. The femoral vein will not pass through the hus. Can I ask you a question in pathology? Maybe we'll see if anyone can answer it. uh we mentioned in the risk factors that

>> [snorts]

>> uh that in the non-modifiable risk factors that male are are more risk males are more at more risk to get atherosclerosis especially compared to um to premenopausal women right so what do you think the the reason behind this why women are have less risk premenopausally

>> yes Iman on

>> maybe because males have a higher blood pressure than females.

>> Okay.

>> Injuries.

>> Okay. This could be one explanation if it is. Yeah. If they have more uh or higher blood pressure. What else? So we said postmenopausal the risk will be almost equal. So what is here? What we are thinking about? What would be the the factor contributing to this?

>> Uh maybe some hormones like uh estrogen.

>> Yeah.

>> Yes. Very good, Muhammad. So estrogen might contribute. Yes. So what's the mechanism? How do how does estrogen will reduce the risk of developing atherosclerosis? Amina, you want to say something? I think you raised your hand or it was the same answer.

>> Yeah, it was the same answer.

>> The same. Okay. So, Muhammad said it is due to estrogen. But how do how does estrogen will reduce the risk of atherosclerosis? Do you know is there any mechanism behind this? Anyone can think about it or give me some possible answers. Yes. Iman or Muhammad?

>> uh maybe because uh the composition of fat. So uh in women the composition of fat in the peripheral uh sides where uh in men it is more in abdominal or visceral fat.

>> Yeah. More yes central maybe central oitive as you mentioned visceral. Yes. Very good. What else Iman?

>> uh because ostrogen is a potent vasoddilator and it is actually related to my previous answer which is about the hypertension because like it is a vasoddilator so there will be less hypertension so less prone to endothelial injuries.

>> Very good. Very good. So so estrogen so there are different mechanisms. So as you mentioned this is one this is one mechanism. Other factors uh estrogen can also improve the lipid profile. um it can enhance the endothelial function and also um uh it reduces inflammation. So these are also other explanations uh behind why female have premenopausal females have less risk to develop less risk to develop atheroscllerosis. Very good. Very good. Uh what else? Also we mentioned in aosclerosis that it is mostly localized in the medium and large blood vessels right the elastic and muscular arteries the medium and the large blood vessels right so why it is more in those specific blood vessels why not in the smaller arteries or arterles is there any explanation behind this or have you have you thought about This remember where the legion specifically is in atherosclerosis in which layer of the artery and remember also which cells contribute to the pathogenesis. This will give you any a hint about the explanation.

Yes. Who's uh

>> it's a question for me. So this is >> regarding the femoral vein. Question which Iman asked does it pass through the adductor hiatus femoral vein or the poplitial vein? These veins are all deep veins and as mentioned in the resource the deep veins are always accompanying the arteries. Okay. So wherever the artery is going the vein will follow the same course. So when it is passing through the hiatus the artery is passing through the adductor hitus the vein along with it passes through the adductor hyus. Only the thing is the flow of blood will in the artery it will be towards the tissue and the flow of venus blood will be in opposite direction. It will be towards the heart. So be it the adductor hiatus or be the adductor canal or the femoral triangle wherever the femoral artery is the femoral vein will be along with it. Okay. So that is the answer for you Iman.

>> So it passes. And the next question is regarding the dorsal metatarsal vein. Are they all connected to the great sapinus vein? Uh and are there four dorsal metatarsal veins and is there one more connecting the small sap?

>> Yes. See there are four dorsal metatarsal veins. Four will join and they form an an arch which is the dorsal venus arch. This dorsal venus arch will receive the metatarsal vein from the medial side of the great toe and that continues as the great sapinus vein from the medial side of the dorsal venus arch. Okay, from the dorsal venus arch medial side it is receiving a dorsal metadoral vein from the medial side of the great toe and this will continue as the great as the great sapinus vein. The same thing happens on the lateral side. From the lateral side of the dorsal venus arch, the metatarsal vein from the little toe will fuse. I mean the these two will fuse and they will form that continuation is uh called the small sapinous vein which goes up. Okay. So great saffinus vein and small sapinous veins these are continuations of the dorsal venus arch. And the dorsal venous arch is formed from four dorsal metatarsal veins. If you see the diagram which is there in the slide, you will understand more clearly. Uh Dr. Aisha. So uh the formoral vein now passes through this adductor hiatasis right?

>> Yes. Yes. Yes.