Anti-hyperlipidemic drugs (Hockerman)

Question 1

Relative size, composition, physiological function of major classes of lipoproteins

Answer 1

Major classes of lipoproteins listed largest to smallest
* Chylomicrons
* Very Low-Density Lipoproteins (VLDL)
* Intermediate Density Lipoproteins (IDL)
* Low Density Lipoprotein (LDL)
* High Density Lipoprotein (HDL)

General Function/Info
* Transport cholesterol & triglycerides in blood
* Apoproteins on surface regulate transport & metabolism

Question 2

Composition & physiological function of chylomicrons

Answer 2

• Primarily triglycerides, very little cholesterol, phospholipid and protein
• transports dietary lipids from gut to liver & adipose tissue

Question 3

Composition & physiological function of VLDL

Answer 3

• Triglycerides, cholesterol, phospholipids, and protein
• Secreted by liver into blood as a source of triglycerides

Question 4

Composition & physiological function of IDL

Answer 4

• Triglyceride-depleted VLDLs
• Intermediate stage in lipoprotein metabolism, can be further processed into LDL

Question 5

Composition & physiological function of LDL

Answer 5

• Mainly cholesterol, very little triglycerides, phospholipids, and protein
• Main cholesterol form in blood; delivers cholesterol to cells

Question 6

Composition & physiological function of HDL

Answer 6

• High protein content, intermediate cholesterol & phospholipids, very little triglyceride
• “Clean up” mechanism; secreted by liver, picks up cholesterol from peripheral tissues and atheromas, returns to liver for cholesterol to be excreted

Question 7

Exogenous pathway for lipid absorption and transport

Answer 7

• Dietary fat enters the small intestine.
• Bile acids and pancreatic lipases break down triglycerides into fatty acids.
• Fatty acids are then re-synthesized into triglycerides within the enterocytes.
• Triglycerides, along with other lipids, form chylomicrons.
• Chylomicrons enter the bloodstream.
• Lipoprotein lipase (LPL) breaks down chylomicron triglycerides.
• Fatty acids are released and travel to adipose tissue.
• Fatty acids are taken up by adipose tissue and stored as triglycerides.

Basically: TG is synthesized and stored in adipocytes when body has excess energy (after meal) and is then broken down when the body needs energy (between meals, during physical activity)

Question 8

Endogenous pathways for lipid absorption and transport

Answer 8

• VLDL is synthesized in the liver using both de novo lipogenesis (creation of fatty acids from non-lipid precursors within the liver) and the uptake of fatty acids from the bloodstream.
• VLDL is released into the bloodstream from the liver.
• In the bloodstream, VLDL undergoes lipolysis, facilitated by lipoprotein lipase (LPL) located in peripheral tissues. This process results in the conversion of VLDL to Intermediate-Density Lipoproteins (IDL).
• IDL can undergo further metabolism in the bloodstream. Triglycerides are removed from IDL, transforming it into Low-Density Lipoproteins (LDL).
• LDL carries cholesterol to various tissues in the body, where it can be utilized for cellular functions.

Question 9

Role of LDL receptor in lipid metabolism, and factors that regulate LDL receptor levels

Answer 9

Role of LDL receptor:
* LDL binds to LDL receptors located on the surface of cells, particularly in the liver.
* The LDL receptor-LDL complex is internalized into the cell through endocytosis.
* Within the cell, LDL is processed, releasing cholesterol for cellular needs.

Factors that regulate LDL receptor levels:
* High intracellular cholesterol levels suppress the synthesis of LDL receptors (to prevent excessive cholesterol uptake)
* Low intracellular cholesterol levels stimulate the synthesis of LDL receptors.

Question 10

Central role of the liver in cholesterol synthesis and lipid distribution

Answer 10

Cholesterol synthesis:
* de novo cholesterol synthesis from acetyl-CoA
* Cholesterol synthesized by liver is incorporated into VLDL

Lipid distribution:
* VLDL transports triglycerides to peripheral tissues
* VLDL –> IDL –> LDL
* LDL carries cholesterol to various tissues for cellular needs

Question 11

Diseases that are associated w/ hyperlipoproteinemia and hypertriglyceridemia

Answer 11

Hyperlipoproteinemia diseases:
* Atherosclerosis (excess accumulation of cholesterol in vascular smooth muscle)
* Can lead to premature coronary artery disease (CAD) & stroke

Hypertriglyceridemia diseases:
* Pancreatitis
* Xanthomas
* Increased risk of coronary heart disease (CHD)

Question 12

recognize molecular structures or statins and indicate which statins are prodrugs

Answer 12

Prodrugs: lovastatin & simvastatin

Question 13

recognize molecular structure of fibrates and indicate which fibrate is a prodrug

Answer 13

Prodrug: fenofibrate

Question 14

strategies for controlling hyperlipidemias and molecular targets

Answer 14

Goals of therapy
* decrease reabsorption of excreted bile acids (bile acid sequestrants)
* decrease secretion of VLDL from liver AKA lipoprotein catabolism (fibrates, niacin, omega 3 fatty acid)
* decrease synthesis of cholesterol (statins)
* increase hydrolysis of lipoprotein triglycerides/lower TG (fibrates)

Question 15

MOA & major side effects for: statins

Answer 15

HMG-CoA Reductase Inhibitors “Statins”
* fluvastatin, rosuvastatin, atorvastatin, lovastatin, simvastatin, pravastatin, pitavastatin

MOA:
* competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis
* upregulate LDL receptors (stimulate synthesis), so LDL delivered to liver and plasma cholesterol is reduced

HMG-CoA reductase function:
Acetyl-CoA –> HMG-CoA reductase –> mevalonic acid –> cholesterol

Side Effects:
* rhabdomyolysis (myopathy) –> dose related; monitor serum creatinine phosphokinase (CPK)
* hepatotoxicity –> monitor serum transaminase activity
* increased incidence of T2D

Question 16

MOA & major side effects for:
bile acid sequestrants

Answer 16

Bile Acid-Binding Resins
* cholestyramine (Queastran) & colestipol (colestid)

MOA:
* inhibit reabsorption of bile acids from intestine by binding bile acids to form insoluble complex excreted in feces
* upregulate LDL receptors in liver

Side Effects:
* constipation
* bloating
* high fiber diet & water helps

Block bile acid in stomach from being absorbed in blood. After binding the bile acids, the complex is excreted in feces. Cholesterol is then taken up to be used to form bile acids which lowers cholesterol levels.

Question 17

MOA & major side effects for: ezetimibe

Answer 17

Cholesterol Absorption Inhibitor

MOA:
* inhibits intestinal absorption of cholesterol from dietary sources & inhibits NPC1L1 which prevents the reabsorption of cholesterol excreted in bile

NPC1L1 function:
* NPC1L1 is expressed on cell surface of enterocytes and binds with cholesterol where cholesterol then enters the enterocyte and is packaged into chylomicrons which transports it into the bloodstream; inhibition of NPC1L1 prevents cholesterol from entering enterocyte, so it sits in intestinal lumen and is then excreted in feces

Side Effects:
* none, generally well-tolerated

Question 18

MOA & major side effects for: bempedoic acid

used as adjunct to statins

Answer 18

ATP-Citrate Lyase Inhibitor (ACL)
* bempedoic acid (nexletol)

MOA:
* inhibits ACL, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway
* increases expression of LDL receptors

Indications:
* heterozygous familial hypercholesterolemia (HeFH)
* ASCVD

Side Effects:
* hyperuricemia
* gout

Question 19

MOA & major side effects for: fibrates

used mainly for high TG

Answer 19

Fibric Acid Derivatives
* clofibrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate

MOA:
* binds to PPAR-α and regulates gene transcription
* reduces LDL, TG
* Increases HDL

Indications:
* hypertriglyceridemia in which VLDL predominate
* second line for mixed hyperlipidemia

Side Effects: (usually minor)
* gallstones
* rhabdomyolysis (use w/ caution w/ statins)

Question 20

MOA & major side effects for: niacin

used mainly for high TG

Answer 20

MOA:
* decreases VLDL, LDL, and TG
* increases HDL

Indications:
* mixed hyperlipidemias/severe cases

Side Effects:
* vasodilation (cutaneous flushing)
* itching
* tingling of upper body & headache w/ initial dosing (treat w/ aspirin or ibuprofen)
* hepatotoxicity (SR preparations)

Question 21

MOA & major side effects for: omega-3 fatty acids

used mainly for high TG

Answer 21

• Lovaza & Omtryg (EPA + DHA); Vascepa (EPA)
• May increase LDL by 4-49%

MOA:
* reduces synthesis of triglyceride in liver
* inhibit esterification of other fatty acids

Indications:
* severe hypertriglyceridemia (>500 mg/dl)

Side Effects:
* can increase LDL-C levels (except meds that only contain EPA, like Vascepa)

Question 22

MOA of PCSK9 inhibitors

used as adjunct to statins

Answer 22

Proprotein Convertase Substilisin Kexin Type 9
* alirocumab, evolocumab

MOA:
* promotes degradation of LDL receptors in liver

Indications:
* adjunct to diet & max tolerated statin therapy in pts w/ ASCVD, HeFH, or HoFH

Side Effects:
* injection site reaction
* arthralgia (joint stiffness)

Question 23

MOA of angiopoietin-like protein 3 inhibitors

Answer 23

• Evinacumab-dgnb

MOA:
* Increases LPL and EL activity by preventing ANGPTL3 mediated inhibition
* Lowers LDL-C

Indication:
* HoFH

Question 24

MOA of mipomersone and primary toxicity

Answer 24

MOA:
* oligonucleotide inhibitor of Apo B100
* hybridizes Apo B100 mRNA in liver and promotes degradation

Indications:
* adjunct to other treatments for pts w/ HoFH (LDLR mutation)

Primary Toxicity:
* high risk of liver damage (restricted Rx program)

Question 25

MOA of lomitapide and primary toxicity

Answer 25

MOA:
* binds to and inhibits MTTP which prevents the assembly of Apo B containing lipoproteins in liver and intestine
* this interferes with chylomicron and VLDL production

Indications:
* adjunct to other treatments for pts w/ HoFH (LDLR mutation)

Primary Toxicity:
* high risk of liver damage (restricted Rx program)