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Skip to 0 minutes and 10 secondsDANIEL MALONE: As you saw in an earlier section, in order to reduce the risk of atherosclerosis, the aim of treatments, such as Atorvastatin, is to reduce circulating LDLs and increase HDLs. In this part, you will see how our drug of interest, Atorvastatin, works to alter these lipoproteins in the blood and what it does to cholesterol levels.

Skip to 0 minutes and 37 secondsAs mentioned earlier, the main site of cholesterol synthesis is the liver. There are a number of steps involved in synthesising cholesterol, but the key step in production of cholesterol is the formation of mevalonate from HMG CoA. Following the production of mevalonate, a number of steps occur in order to form cholesterol. As mentioned by David in the chemistry section, the synthesis of mevalonate HMG CoA is catalysed by the enzyme HMG CoA reductase. Atorvastatin is a competitive inhibitor of HMG CoA reductase. That is, it competes for the same sites on the HMG CoA reductase enzyme as the natural substrate, which is HMG CoA. This reduces the formation of mevalonate, thus the formation all cholesterol.

Skip to 1 minute and 40 secondsSo let's look at the effects Atorvastatin has on lipoproteins in the body as a consequence all this inhibition of HMG CoA reductase and, therefore, the reduction in cholesterol synthesis. Since VLDLs are substantially made up of cholesterol, if cholesterol synthesis in the liver is decreased, the liver will make less VLDLs. And less VLDLs will be secreted by the liver. Since LDLs are made when VLDLs lose some of their triglycerides, LDL numbers will also decrease. Since the liver is making less cholesterol and requires cholesterol for various functions, such as bile acid synthesis, there will be more LDL receptors made, and this means that more LDLs will enter cells in the liver.

Skip to 2 minutes and 43 secondsAnother consequence of less synthesis of cholesterol in the liver is that HDL synthesis is increased so that HDLs can scavenge cholesterol from around the body and return it to the liver. The end result of this is a decrease in circulating LDLs by 20 to 60%, depending on the dose of Atorvastatin given plus other factors, like individual variability. There is also a modest increase in HDL by 2 to 14%. So to recap, inhibiting HMG CoA reductase, and thus reducing production of cholesterol in the liver, has three main effects on lipoproteins. Firstly, it means less VLDLs are made in the liver.

Skip to 3 minutes and 36 secondsSecondly, since the liver requires cholesterol, there are more receptors that bind to LDLs and take the LDLs into the cells in the liver. And finally, the liver secretes more HDLs in an attempt to acquire more cholesterol from around the body and return it to the liver. Just as a reminder, as a consequence all these effects on lipoproteins, the progression of atherosclerosis is, therefore, decreased. So to summarise, in this section, you learned how Atorvastatin inhibits a key enzyme involved in cholesterol synthesis. And that, as a consequence of this, lipoproteins in the blood are altered so that more cholesterol is returned to the liver.

Heart disease pharmacology

Watch Dan explain how atorvastatin works to alter the LDL and HDL lipoproteins in the blood and what this does to cholesterol levels.

As you make your way through the course, you may like to return to this video and replay particular sections to review Dan’s presentation on heart disease pharmacology.

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This video is from the free online course:

The Science of Medicines

Monash University