Lipid-lowering medications: Statins

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Introduction0:00–0:25

Statins lower overall lipid levels in the body, and work by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting step of cholesterol metabolism.
They are an incredibly important class of medications because they’ve been shown to decrease complications associated with cardiovascular disease like strokes, heart attacks, and peripheral vascular disease.
Although it’s got a bad reputation, cholesterol is actually a critical component of our cells and is used to build the cell membrane.

Pathophysiology0:25–4:10

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.
Okay! So, statins are a group of medications that are used to prevent these complications.

Mechanism of action4:10–5:45

Common statins include simvastatin, lovastatin, and pravastatin, while the newer atorvastatin and rosuvastatin are more potent, with a longer half-life.
Now, all of the statins work by inhibiting cholesterol synthesis in the liver. They are structurally similar to HMG-CoA, so they can bind to HMG-CoA reductase and prevent the actual substrate from binding.
Since HMG-CoA reductase is the rate-limiting step, statins can dramatically decrease cholesterol synthesis in the liver.
Now when the liver can’t make any more cholesterol, it will try to get it from the rest of the body. So hepatic cells will increase the number of LDL receptors on their surface, which facilitates the uptake of cholesterol-rich LDLs, thus further lowering cholesterol level in the blood.
These LDL receptors also increase the uptake of VLDLs to a smaller degree, which provides a moderate decrease in triglyceride level.
Next, to get even more cholesterol, the liver will increase production of HDLs, which will carry cholesterol back from the peripheral tissues.
So to sum it up, there’s a major decrease in LDL, a major increase in HDL, a major decrease in cholesterol, and a moderate decrease in VLDL and triglycerides.
Statins are metabolized by cytochrome p450 enzymes in the liver, so medications that enhance or inhibit their activity should be avoided.

Side effects5:45–6:43

For side effects, statins are very well tolerated. Common side effects include gastrointestinal symptoms and rashes.
Some of the more serious toxicities of statins include myalgia, or muscle pain; and rhabdomyolysis, or muscle breakdown.
This side effect is thought to be due to the fact that a downstream product of mevalonic acid is farnesyl pyrophosphate, which is required for the production of Coenzyme Q.
This is a necessary cofactor in the electron transport chain of all cells. When the electron transport chain experiences decreased functionality, less overall ATP will be produced.
This will affect the energy-intensive cells like muscle cells more heavily, so we end up with muscle damage. Next, although rare, statins can be hepatotoxic, especially in people who already have liver diseases.
Finally, these medications are teratogenic so they should be avoided in pregnant women. Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharm facts!

Memory Palace6:43–8:19

So first, let’s set the scene at a train station, for statins. Now, there’s a top rail track and a bottom rail track.
On the top rail, let’s put a train that’s carrying heavy metal crates representing HDL. The fact that it’s on the higher track will help you remember statins increase HDL.
Now on the lower track, we have decreased LDL and VLDL. So let’s have a train full of LDL wooden crates, and another one with cardboard boxes for VLDL.
Now, notice how there are a lot more wooden crates? That’s because statins have a much larger effect on LDL compared to VLDL.
Okay moving on, let’s decorate all 3 trains with happy little hearts since they all benefit the cardiovascular system and help prevent strokes and heart attacks.
So guarding the train station, we have a soldier with a Heavy Machine Gun, or HMG. He’s reduced to tears because he hates his job, which also represents the main enzyme affected by these drugs: HMG-CoA reductase.
For the important side effects, the soldier has been target practicing with a cardboard cutout of a super muscular lady, who represents the muscular problems like myalgias and rhabdomyolysis.
She’s holding a liver over her head to help you remember these medications are occasionally hepatotoxic. Finally, she’s pregnant to help you remember statins are teratogenic.

Review8:19–8:56

All right, as a quick recap, statins work to lower overall lipid levels in the body, and function by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting step of cholesterol synthesis.
They decrease LDL and VLDL, while increasing HDL, which leads to a large decrease in cholesterol and a mild decrease in triglyceride levels.
They are commonly used to prevent heart attacks, strokes, and peripheral vascular disease. Their main side effects include gastrointestinal upset and rashes, muscle pain, and in rare cases, liver damage.
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.

Mind Map8:56–9:07

Stay tuned for the answers after the credits.