CVS: Lipid-lowering

Question 1

Rank from lightest to heaviest.

VLDL, HDL, LDL, CM, IDL, FFA/albumin

Answer 1

1. CM
2. VLDL
3. IDL
4. LDL
5. HDL
6. FFA/albumin

Question 2

Where do chylomicrons form?

What do they contain?

Where do they go?

Answer 2

Mucosal epithelial cells of the small intestine.

Mainly dietary lipids.

Go to adipose tissues for storage.

Question 3

Where do VLDLs form?

What do they contain?

Where do they go?

Answer 3

Hepatocytes.

Endogenous lipids.

Adipocytes for storage, muscle cells for ATP production.

Question 4

Where do IDLs form?

What do they contain?

Where do they go?

Answer 4

AKA VLDL remnants.

Derived from TG depletion of VLDL.

Liver for reprocessing, or lose more TG to become LDL.

Question 5

Where do LDLs form?

What do they contain?

Where do they go?

Answer 5

Depletion of TG from VLDL.

Cholesterol.

Deposit cholesterol in and around smooth fibres in arteries, forming fatty plaques.

Question 6

Where do HDLs form?

What do they do/ where do they go?

Answer 6

Liver.

Remove excess cholesterol from body cells and blood and transports cholesterol to the liver for elimination.

Question 7

Name 5 classes of lipid-lowering agents.

Answer 7

1. Niacin
2. Fibrates
3. Resins
4. HMG-CoA Reductase Inhibitors
5. Inhibitor of intestinal sterol absorption

Question 8

What is the MOA of niacin (nicotinic acid, vit B3)?

Answer 8

1. Niacin strongly inhibits lipolysis in adipose tissue. Thus, both plasma TG in VLDL and cholesterol in VLDL and LDL are lowered. Fat is not actually released.
2. Niacin treatment increases HDL-cholesterol levels potently.
3. By decreasing circulating fibrinogen and increasing tPA, niacin can reverse thrombosis associated with hypercholesterolemia and atherosclerosis.

Question 9

Clinical uses of niacin?

Answer 9

1. Type IIb hyperlipoproteinemia

2. Type IV hyperlipoproteinemia

Question 10

Pharmacokinetics of niacin?

Answer 10

In the body, niacin -> nicotinamide.

Question 11

Adverse effects of niacin?

Answer 11

1. Intense cutaneous flush and pruritus (cos small capillaries suddenly expand)
2. Hyperuricemia and gout (effect may be due to the inhibition effect of niacin on uricase, an oxidizing enzyme of uric acid)

Question 12

Name 3 fibrates.

Answer 12

1. Gemfibrozil
2. Fenofibrate
3. Clofibrate

Question 13

What is the MOA of fibrates?

Answer 13

1. Fibrates are ligands for the peroxisome proliferators-activated alpha protein (PPARa).
2. Interacting with PPARa results in increased LPL activity.
3. LPL activity increase, plasma TG decrease.
4. VLDL levels decreased due to decreased secretion by the liver.
5. HDL levels rise moderately.

Question 14

Clinical uses of fibrates?

Answer 14

Treat hyperTG with VLDL elevation (esp dysbetalipoproteinemia).

Question 15

Adverse effects of fibrates?

Answer 15

GI effects: nausea
Skin rashes
Gallstones
Myositis (inflammation of the muscles that you use to move your body)

Question 16

Name 2 resins.

Answer 16

Colestipol

Cholestyramine

Question 17

What is the MOA of bile-acid binding resins?

Answer 17

1. Anion exchange resins bind negatively charged bile acids and bile salts in the small intestine.
2. Lowering the bile acid concentration causes hepatocytes to convert cholesterol to bile.
3. Activates an increased hepatic uptake of cholesterol containing LDL, lowering plasma LDL levels.
4. May increase VLDL, but little effect on HDL.

Question 18

Clinical uses of resin?

Answer 18

Treat primary hypercholesterolemia (IIa)

+Niacin: treat LDL elevations in patients with combined hyperlipidemia (IIb)

Question 19

Administration of resin is…

Answer 19

Oral only.

Question 20

Adverse effects of resin?

Answer 20

1. GI effects: constipation, nausea, flatulence

2. Impaired absorption of vit ADEK

Question 21

Name 4 HMG-CoA reductase inhibitors.

Answer 21

Lovastatin
Simvastatin
Pravastatin
Fluvastatin

Question 22

What is the MOA of HMG-CoA reductase inhibitors?

Answer 22

1. Strong affinity to the enzyme.
2. Inhibit HMG-CoA reductase, which is the RDS in cholesterol synthesis.
3. Increase in LDL receptors: depletion of intracellular cholesterol causes cell to increase the number of specific cell-surface LDL receptors that can bind and internalise LDLs in circulation.

Question 23

Pharmacokinetics of HMG-CoA reductase inhibitors?

Answer 23

Oral, first-pass extraction.

Give in evening; cholesterol synthesis is at its peak in the fasted state (during sleep).

Question 24

Clinical uses of HMG-CoA reductase inhibitors?

Answer 24

Lowering plasma cholesterol levels in all types of hyperlipidemias.

Reduce risk of coronary events and mortality in patients with ischemic heart disease.

Question 25

Adverse effects of HMG-CoA reductase inhibitors?

Answer 25

1. Liver: biomedical abnormalities in liver function (look at LFT results)
2. Muscle: myopathy and rhabdomyolysis (check for muscle soreness after taking drug

Question 26

Contraindications for HMG-CoA reductase inhibitors?

Answer 26

Anyone who is “growing”:

Pregnant
Nursing mothers
Children
Teenagers

Question 27

Name the inhibitor of intestinal sterol.

Answer 27

Ezetimibe aka Zetia

Question 28

What is the MOA of Ezetimibe?

Answer 28

Selective inhibitor of cholesterol transport protein, NPC1L1.

Question 29

What are the clinical uses of Ezetimibe?

Answer 29

Reduce LDL

If used alone, can reduce 18%.
Can use in combination with simvastatin (vytorin=simvastatin+ezetimibe)

Question 30

Pharmacokinetics of Ezetimibe?

Answer 30

Readily absorbed.

Conjugated in the intestinal wall to an active glucuronide.

Question 31

Adverse effects of Ezetimibe?

Answer 31

Low incidence of reversible impaired liver function.

Question 32

Will Ezetimibe work with no dietary cholesterol?

Answer 32

Yes.