Pharmacology of lipid-lowering agents - Indra Flashcards
What are estradiol, vitamin D, and bile acids synthesized from?
cholesterol
What are the differences between MUFA’s, pUFA’s, and saturated fatty acids?
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.
What are chylomicrons?
They are in foods, and contain cholesterol esters and TG’s
What form are fatty acids in while stored in skeletal muscle or fat?
TG’s, or used for energy in skeletal muscle.
What enzyme breaks down TG’s to fatty acids?
lipoprotein lipase
What lipoprotein is the largest in size and the smallest in density?
The chylomicron
What lipoprotein is the smallest in size and highest in density?
HDL
What lipoproteins contain B-100?
VLDL, IDL, LDL
What lipoprotein contains B-48?
The chyomicron
What lipoprotein contains A-II?
HDL
When TG are stripped from the chylomicron, what happens to the chylomicron remnant?
- 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.
What happens with free cholesterol and CE’s and phospholipids?
Extra hepatic tissues transfer these to ApoAI containing particles. These dock to ATP-ABC transporter, and are transformed into HDL by lysolecithin
What do ABCA1 and ABCG1 do?
They are both involved with HDL formation, ABCA1 in initial and ABCG1 in already formed HDL.
What is the reverse cholesterol pathway?
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.
Does HDL also prove harmful>
Yes, it can also transfer CE’s to LDL and IDL
What do the LDL receptors on the liver do?
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.
What class of LDLR mutation is a Clatharin binding defect?
A class 4. This would help the LDL be internalized.
What would be a sign that would point you to familial hypercholesterolemia?
Xanthomas
How does PCSK9 affect LDL receptors?
They bind LDL receptors to enhance their lysosomal degradation, which increases serum LDL levels. = Bad.
What do monoclonal antibodies do to to PCSK9?
They inhibit PCSK9, which means that the receptors are not broken down as much, and the serum LDL is lowered. = Good.
What is the mevalonate pathway?
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.
What does the binding of Scap to SREBP cause? Snap to cholesterol?
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.
What agent acts against the lipoprotein lipase, against the formation of VLDL, and in the liver?
FIbrates, such as gemfibrozil and fenofibrate. This increases the removal of TG’s/
What agent acts by inhibiting the absorption of cholesterol from the GI tract by inhibiting the NPC1L1?
Ezetimibe (in zetia)
What agents decrease the synthesis of cholesterol and the secretion of VLDL, and increase action of LDL receptors?
Both statins and PCSK9i (statins act against the mevalonate pathway.
What agents bock conversion of HDL to LDL?
CETPi (anacetrapib - zetia)
What agents decrease the secretion of VLDL and LDL, and increase formation of HDL?
Nicotinic acid
What agents promote bile acid secretion and fecal elimination of bile acids?
Bile-acid binding resins.
What agents decrease VLDL synthesis, decrease TG levels, and possibly stimulate B oxidation of FA’s and LPL activity?
Omega-3 fatty acids
What are MTTp inhibitors?
Lomitapide - ho familial hypercholesterolemia
What is the antisense mRNA Apo-B-100 inhibitor?
mipomersen - ho familial hypercholesterolemia
What are SLCO1B1 mutations associated with?
60% of statin-induced myopathies
What does grapefruit have to do with myopathies?
They inhibit 3A4, and cause statins that use 3A4 for metabolism to build up, greatly increasing the risk of myopathies.
Which statins are ok to take with grapefruit?
Pitavastatin
Pravastatin
Rosuvastatin
What should you do if creatine kinase is elevated 10x ULN?
DC statins.
