Miscellaneous lipid-lowering medications

Lipid-lowering medications work to decrease levels of cholesterol and triglycerides in the body. Several medications fall outside the more commonly used classes like statins and fibrates, so in this video, we're going to discuss the bile acid resins, niacin or vitamin B3, ezetimibe, and the PCSK9 inhibitors.Although it’s got a bad reputation, cholesterol is actually a critical component of our cells and is used to build the cell membrane.

It also has other uses like the synthesis of: steroid hormones, vitamin D, and bile. Normally, we get our cholesterol from the food we eat, but it can also be synthesized by the liver.

So when we eat a box of chili fries, the fats and cholesterol are absorbed in the small intestine. However, they’re not water soluble, so they can’t travel freely in the blood.

To fix this, our body makes shipping boxes called lipoproteins. These containers consist of a shell made of phospholipids and protein tags that act as instructions for their destination.

So after absorption, the small intestinal cells package the fats and cholesterol into the largest but least dense lipoproteins, called chylomicrons.

These are released into the lymphatic system and then enter the bloodstream via the subclavian vein. Then they travel through the blood to reach adipose tissue and the liver.

Now, the liver can also synthesize intrinsic cholesterol through the mevalonate pathway, which happens in the smooth endoplasmic reticulum of liver cells.

It begins with 2 acetyl-CoA molecules getting joined together by the enzyme acetyl-CoA acyl-transferase. The result is a 4-carbon molecule called acetoacetyl-CoA.

Next, the enzyme HMG-CoA synthase combines acetoacetyl-CoA and acetyl-CoA to form a 6-carbon molecule called 3-hydroxy-3-methylglutaryl CoA, or HMG-CoA.

Then, an enzyme called HMG-CoA reductase reduces HMG-CoA into mevalonate. This step with HMG-CoA reductase is the rate-limiting step of cholesterol synthesis.

In other words, the rate of this reaction determines the overall rate of cholesterol synthesis, it’s like the slowest step of an assembly line in a factory.

Mevalonate is the precursor molecule that will eventually become cholesterol. Okay, in the liver, cholesterol and a lot of triglycerides are packed into the next kind of lipoproteins called very-low-density lipoproteins or VLDL, which are smaller and more dense than chylomicrons.

This package is sent into the bloodstream and carry the energy-rich triglycerides to the rest of the body. Now, after unloading their triglycerides, the VLDL and the remaining cholesterol become a new kind of lipoprotein, called a low-density lipoprotein, or LDL, which are even smaller and more dense than VLDL.

These will travel around the bloodstream and deliver cholesterol to cells in the rest of the body. The final lipoprotein is the HDL, or high-density lipoprotein, which are smaller but denser than LDLs.

These are like the boxes you get when you try to return an item you bought online. In this case, the liver produces HDL and released them into the blood, where they pick up excess cholesterol from the peripheral tissues and brings them back to the liver.So in essence, it’s the opposite of LDL, which carries cholesterol from the liver to the peripheral tissues.

Now, the tissues in the body will take in the LDLs, as well as the cholesterol that’s contained in them. So, if we have too much LDL, we get cholesterol build up in these tissues.

One of the most clinically relevant tissues is the endothelium that lines the blood vessels.Increased cholesterol here will lead to the formation of fatty deposits called plaques, and these will increase the risk of cardiovascular complications like strokes, myocardial infarctions, and peripheral vascular disease.

Now, our miscellaneous lipid lowering agents act at several points during lipid metabolism. The first group of medications are the bile acid resins like cholestyramine, colestipol, and colesevelam.

These are large, positivity charged molecules that bind to the negatively charged bile acid in the intestine. Being stuck to the resin keeps bile acid from being reabsorbed, and they get excreted with the stool.

So, since we are depleting bile acid, the liver will compensate by increasing the production of bile salts, and this uses up a lot of cholesterol.

To get more cholesterol from the rest of the body, the hepatic cells increase the number of LDL receptors on their surface, which facilitates the uptake of cholesterol-rich LDLs, thus further lowering cholesterol levels in the blood.

However, the liver also increases the synthesis of HMG-CoA reductase, which synthesizes more cholesterol. This means these medications are not as effective as the statins in decreasing LDL cholesterol, since statins increase the LDL receptors and inhibit HMG-CoA.

So bile acid resins are usually used together with statins. Next, the LDL receptors also very slightly increase the uptake of VLDL.Although these drugs can also cause a very small increase in HDL, their main use is to treat high levels of LDL cholesterol.Side effects of bile acid resins include gastrointestinal upset and decreased absorption of fat soluble medications like digoxin, and vitamins such as A,D,E and K.

Speaking of vitamins, the next lipid lowering agent is vitamin B3, or niacin. Niacin works by inhibiting lipoprotein lipase in adipose tissue.

These lipases cut up the triglycerides stored within adipocytes and release them as free fatty acids. The liver uses these free fatty acids to create triglycerides which in turn forms VLDLs.

Niacin will decrease the amount of free fatty acids released, which leads to a moderate decrease in VLDL and LDL levels.

Finally, niacin can cause a moderate increase in HDL by decreasing its uptake by the liver. Niacin has an interesting side effect called “niacin flush,” which leads to a red, flushed face, and pruritus (or itching).

Besides the discomfort, it’s more or less harmless. To combat this issue, people on niacin take NSAIDs, or non-steroidal anti-inflammatory drugs, to prevent these symptoms.

Other side effects of niacin include high blood sugar and high uric acid levels in the blood. Next up is ezetimibe.

The mechanism of ezetimibe is not fully understood, but it’s known to block the critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 protein, on the gastrointestinal tract epithelial cells at the small brush border.

This medication does not affect VLDL or HDL and is mainly used to treat high levels of LDL.However, ezetimibe by itself does decrease overall LDL levels and it’s typically used in combination with other lipid lowering agents like statins.Side effects of ezetimibe include gastrointestinal upset, and the rarer liver damage.

Okay, lastly we have the newest brand of lipid lowering agents called PCSK9 inhibitors. These are medications, like alirocumab and evolocumab, are antibodies that target the PCSK9 protein.

PCSK9 gets secreted by liver cells and bind to LDL receptors on the cell’s surface, which mediates the uptake and breakdown of LDL receptors intracellularly.

So PCSK9 inhibitors bind to these proteins and prevent LDL-receptor degradation. This mechanism increases the overall quantity of LDL receptors on liver cells and thus causes a large decrease in LDL in the bloodstream, while providing a slight decrease in VLDL and a slight increase in HDL.

So just like the bile acid resins, they are indicated for people with high levels of LDL. The downside to using PCSK9 inhibitors include the fact that they must be given via injection every 2-4 weeks.

They have also been associated with myalgias, or muscle pain, and neurocognitive effects like delirium and dementia. Since they are so new, not many people are on them; however, researchers predict they may serve as reliable medications for people who don’t respond to statins or other lipid lowering medications.

Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharm facts! First, let’s go to a butcher shop!

The butcher has a giant knife for niacin, and he’s cutting into a big slab of fatty pork, to help you remember that it targets lipoprotein lipase.

The pieces he cuts off are put into boxes; we’ll use metal boxes for the very dense HDLs, wooden boxes for the LDLs, and paper boxes for the least dense VLDLs.

So the butcher put the meat into a metal box, a paper box, and a wooden box, since niacin can be used for treating low HDL, high VLDL, and LDL.For side effects, let’s have his face flush red to represent niacin flush.

He’s eating a large candy bar to represent hyperglycemia, and the candy has uric acid crystals on it to represent hyperuricemia.

Okay, next up is ezetimibe, and let’s have another butcher with a meat tenderizer, since he’s making the meat ez to eat.

Let’s put some paper towels under the meat to help you remember ezetimibe affects the absorption of cholesterol in the small intestine.

The tenderized meat goes into a LDL wooden box since this drug is used for high LDL. For side effects, let’s have him hammer away at a piece of liver, which represents hepatotoxicity.

Okay moving on, at the back of the shop, there’s a pile of raisins that’s used to add flavor to the meat. These raisins are drenched in bile because they represent the bile acid resins.

Now these raisins are put into an LDL wooden box since they are also used to treat high LDL. For side effects, let’s put a big stick of butter by the raisins, and there’s little pills and vitamins sticking out of it.

This will help you remember that bile acid resins decrease absorption of lipid soluble drugs and vitamins. Finally, let’s talk about the PCSK9 inhibitors.

Since these drugs, like alirocumab and evolocumab, end in “cumab” we’ll use a man combing his hair to represent them. Now, this man is buying meat from the butcher, and he’s got a very large wooden box of meat since PCSK9 inhibitors are used to treat high LDL.

For side effects, the fact that he is obsessively combing his hair makes him appear a little crazy, so this will help you remember the neurocognitive side effects like dementia.

His arms are big and red to help you remember these drugs can cause myalgia. ##SummaryAll right, as a quick recap, lipid-lowering medications work to decrease levels of cholesterol and triglycerides in the body.

The miscellaneous lipid lowering medications interfere at different steps of lipid digestion and metabolism. The bile acid resins and PCSK9 inhibitors increase LDL receptors; ezetimibe blocks cholesterol absorption; and niacin inhibits lipolysis, VLDL synthesis, and HDL uptake in the liver.

But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Stay tuned for the answers after the credits. high LDL for side effects The fact that he's obsessively combing his hair makes him appear a little crazy So this will help you remember the neurocognitive side effects like dementia his arms are big and red to help you remember these drugs can cause myalgia All right As a quick recap lipid lowering medications work to decrease levels of cholesterol and triglycerides in the body The patient is acelle the lipids lowering medications interfere at different steps of lipid digestion and metabolism The bile acid resins and PCSK nine inhibitors increase LDL receptors Ezetimibe blocks cholesterol absorption and niacin inhibits lipolysis V LDL synthesis and HDL uptake in the liver But wait there's more here's a mind map with all the mnemonics Go ahead and pause the video so you can test yourself to see what you remember and stay tuned