Pharmacology of lipid-lowering agents - Indra

Question 1

What are estradiol, vitamin D, and bile acids synthesized from?

Answer 1

cholesterol

Question 2

What are the differences between MUFA’s, pUFA’s, and saturated fatty acids?

Answer 2

They are all triglycerides, but the saturated FA’s do not have double-bonded carbons, while the MUFA has one, and the PUFA’s have multiple. The more unsaturation, the better it seems like.

Question 3

What are chylomicrons?

Answer 3

They are in foods, and contain cholesterol esters and TG’s

Question 4

What form are fatty acids in while stored in skeletal muscle or fat?

Answer 4

TG’s, or used for energy in skeletal muscle.

Question 5

What enzyme breaks down TG’s to fatty acids?

Answer 5

lipoprotein lipase

Question 6

What lipoprotein is the largest in size and the smallest in density?

Answer 6

The chylomicron

Question 7

What lipoprotein is the smallest in size and highest in density?

Answer 7

HDL

Question 8

What lipoproteins contain B-100?

Answer 8

VLDL, IDL, LDL

Question 9

What lipoprotein contains B-48?

Answer 9

The chyomicron

Question 10

What lipoprotein contains A-II?

Answer 10

HDL

Question 11

When TG are stripped from the chylomicron, what happens to the chylomicron remnant?

Answer 11

• It is taken up by the liver, which recycles the remaining lipids and synthesizes its own CEs and TG, which needs to be distributed to the tissues.
• Packages into VLDL and releases into blood stream.
• Lipoprotein lipase strips TG’s from this (and these fatty acids are used by the tissues) and the particle is now known as IDL.
• 2/3 of IDL go to the liver and are taken up by a receptor like the chylomicron remnant was.
• 1/3 of IDL loses enough TG’s to become LDL, which distributes cholesterol and CEs to tissues.

Question 12

What happens with free cholesterol and CE’s and phospholipids?

Answer 12

Extra hepatic tissues transfer these to ApoAI containing particles. These dock to ATP-ABC transporter, and are transformed into HDL by lysolecithin

Question 13

What do ABCA1 and ABCG1 do?

Answer 13

They are both involved with HDL formation, ABCA1 in initial and ABCG1 in already formed HDL.

Question 14

What is the reverse cholesterol pathway?

Answer 14

It occurs when HDL forces scavenger receptors on hepatocytes, and forces them to release their cholesterol/CEs to the liver, where it is excreted into the bile as free cholesterol or as bile salts.

Question 15

Does HDL also prove harmful>

Answer 15

Yes, it can also transfer CE’s to LDL and IDL

Question 16

What do the LDL receptors on the liver do?

Answer 16

They clear about 70% of the circulating LDL. Circulating LDL is the number you want to lower, not the total LDL levels. It is important in homeostasis.

Question 17

What class of LDLR mutation is a Clatharin binding defect?

Answer 17

A class 4. This would help the LDL be internalized.

Question 18

What would be a sign that would point you to familial hypercholesterolemia?

Answer 18

Xanthomas

Question 19

How does PCSK9 affect LDL receptors?

Answer 19

They bind LDL receptors to enhance their lysosomal degradation, which increases serum LDL levels. = Bad.

Question 20

What do monoclonal antibodies do to to PCSK9?

Answer 20

They inhibit PCSK9, which means that the receptors are not broken down as much, and the serum LDL is lowered. = Good.

Question 21

What is the mevalonate pathway?

Answer 21

It is a key intermediate as Acetyl CoA is converted to cholesterol
A transcription factor SREBP is key that regulates the expression of many of the genes involved in cholesterol biosynthesis. This is a target of the statins.

Question 22

What does the binding of Scap to SREBP cause? Snap to cholesterol?

Answer 22

Snap to SREBP means that cholesterol synthesis genes will be activated. If bound to cholesterol, Scap binds to SREBP and binds to Insig. Cholesterol is not formed as the complex stays in the ER.

Question 23

What agent acts against the lipoprotein lipase, against the formation of VLDL, and in the liver?

Answer 23

FIbrates, such as gemfibrozil and fenofibrate. This increases the removal of TG’s/

Question 24

What agent acts by inhibiting the absorption of cholesterol from the GI tract by inhibiting the NPC1L1?

Answer 24

Ezetimibe (in zetia)

Question 25

What agents decrease the synthesis of cholesterol and the secretion of VLDL, and increase action of LDL receptors?

Answer 25

Both statins and PCSK9i (statins act against the mevalonate pathway.

Question 26

What agents bock conversion of HDL to LDL?

Answer 26

CETPi (anacetrapib - zetia)

Question 27

What agents decrease the secretion of VLDL and LDL, and increase formation of HDL?

Answer 27

Nicotinic acid

Question 28

What agents promote bile acid secretion and fecal elimination of bile acids?

Answer 28

Bile-acid binding resins.

Question 29

What agents decrease VLDL synthesis, decrease TG levels, and possibly stimulate B oxidation of FA’s and LPL activity?

Answer 29

Omega-3 fatty acids

Question 30

What are MTTp inhibitors?

Answer 30

Lomitapide - ho familial hypercholesterolemia

Question 31

What is the antisense mRNA Apo-B-100 inhibitor?

Answer 31

mipomersen - ho familial hypercholesterolemia

Question 32

What are SLCO1B1 mutations associated with?

Answer 32

60% of statin-induced myopathies

Question 33

What does grapefruit have to do with myopathies?

Answer 33

They inhibit 3A4, and cause statins that use 3A4 for metabolism to build up, greatly increasing the risk of myopathies.

Question 34

Which statins are ok to take with grapefruit?

Answer 34

Pitavastatin
Pravastatin
Rosuvastatin

Question 35

What should you do if creatine kinase is elevated 10x ULN?

Answer 35

DC statins.