Dyslipidemia Drugs

Question 1

Explain how the body absorbs fat and how is it distributed in extra hepatic tissues?

Answer 1

1. Lipids are packaged and shipped by intestinal cells into the lymphatics via chylomicrons, packaged as triglycerides.2. Cholesterol is converted to cholesterol esters and packaged into the center of the chylomicrons3. Chylomicrons deliver these into extra hepatic tissues4. Lipoprotein lipase (LPL) converts these triglycerides into free fatty acids which then can be used by heart and muscles for metabolism

Question 2

How are chylomicrons recycled by the liver?

Answer 2

Taken up by hepatocytes via the LDL receptor through receptor mediated endocytosis

Question 3

What lipoprotein does LDL bind to?

Answer 3

ApoE

Question 4

What is the fate of cholesterol in the liver?

Answer 4

Can be packaged and sent to extra hepatic tissues via chylomicrons or can be secreted as bile

Question 5

What happens in the hepatocytes when there is low cholesterol?

Answer 5

It can be made by HMG CoA reductase enzyme, first intermediate in cholesterol synthesis is mevalonic acid

Question 6

Explain what lipoprotein is associated with atherosclerosis

Answer 6

B100 is a lipoprotein found in LDL and VLDL which carry triglycerides to the peripheral tissue, these are associated with atherosclerosis

Question 7

How are LDLs formed?What does LDL contain?

Answer 7

VLDLs go into the extra hepatic tissue where they lost their triglycerides through enzymatic release by LPL, as VLDL lose their triglycerides they form into LDLs.It contains cholesterol esters.

Question 8

How does LDL distribute cholesterol in the body and which organ takes the most of it?

Answer 8

Organs that require cholesterol for their metabolic needs up regulate LDL receptors to take in LDLs for cholesterol, similarly tissues that don’t need cholesterol down regulate these LDL receptors.70% of the LDLs are taken up by liver

Question 9

What does HDL do? Name the enzyme important for HDL function.

Answer 9

Extracts cholesterol from peripheral tissues and takes it to liver, the enzyme that catalyzes free cholesterol to cholesterol esters to be packaged into HDL is LCAT, lecithin cholesterol acetyl transferaseIt also loads up LDL and VLDL with cholesterol esters so they can be transported back to the liver

Question 10

How are HDL endocytosed in the liver?

Answer 10

Via scavenger 1 receptor

Question 11

Where does statins exhibit most of their effects?

Answer 11

They have extensive first pass metabolism so most of their effects are exhibited in the liver where they inhibit HMG CoA reductase, this causes decreases malovanic acid and decreased endogenous cholesterol, as a result hepatocytes up regulate LDL receptors

Question 12

What are statins most effective for?

Answer 12

Ideally they decrease LDL, triglycerides and increase HDL however the most potent effect is in decreasing LDL

Question 13

What is the first line of treatment for hypercholestrolemia?

Answer 13

Lifestyle changes

Question 14

What treatment should be prescribed when lifestyle changes are not enough?

Answer 14

Statins, even if LDL is normal we should prescribe statins to patients to avoid atherosclerosis in future. Statins are the only medication that has been proved to improve survival in patients with CV diseases

Question 15

What other conditions can we use statins for?

Answer 15

Diabetes and in patients that have a history of stroke

Question 16

When are statins contraindicated?

Answer 16

Pregnancy and breast feeding mothers, they are teratogenic

Question 17

Major side effect of statin?

Answer 17

Myalgias, elevations in serum CK, liver enzymes are also sometimes elevated.

Question 18

Explain the metabolism of statins

Answer 18

CYP450 metabolism except for pravastatin

Question 19

What are the indications for using cholestyramine and ezetimibe?

Answer 19

Usually used as an adjunct therapy with statins to further improve long term CV outcomes

Question 20

Name the cholestyramine similar agents

Answer 20

Cholestyramine, colestipol, colesevam

Question 21

Explain their MOA

Answer 21

Bile acids that are formed from cholesterol are secreted into the intestine and 95% of it is reabsorbed in the ileum, cholestyramine are bile acid binding resins that prevents its reabsorption back into the liver

Question 22

What is the effect of cholestyramine on liver?

Answer 22

Liver has to upregulate LDL receptors and its endogenous cholesterol production.

Question 23

Compare and contrast the effect of statin and cholestyramine on liver

Answer 23

Statins inhibit endogenous cholesterol production, cholestyramine increases endogenous liver production, HMG CoA reductase is upregulated

Question 24

What are the adverse effects of cholestyramine drugs?

Answer 24

1. Gall stones2. Causes an increase in production of triglycerides, patients with hypercholesterolemia and hyperlipidemia should not be prescribed cholestyramine, this manifests as increase in VLDLs3. GI upset, constipation and bloating

Question 25

How can cholestyramine inhibit absorption of other drugs?

Answer 25

Continuous bile reabsorption can cause bile levels to go down in the GI leading to steatorrhea. As a result fat soluble vitamins ADEK may not be absorbed this can lead to bleeding disorder due to Vitamin K deficiency for example.Bile acid resins decrease numerous drugs resorption, especially statins, should be given 4 hours apart.

Question 26

Explain the MOA of ezetimibe and what are its effects on the body as a result.

Answer 26

Ezetimibe blocks intestinal absorption of dietary cholesterol, causes liver to up regulate LDL receptors and increase endogenous cholesterol production.Number of chylomicrons decrease.

Question 27

What are the adverse effects of eczitimide?

Answer 27

It does not cause gall stones, hyperlipidemia and steatorrhea, however it causes diarrhea. It also causes an increase in AST and ALT

Question 28

What are PCSK9 inhibitors

Answer 28

Normally LDL receptors are broken down by an enzyme called PCSK9, PCSK9 inhibitors the breakdown of LDLs

Question 29

What is an example of PCSK9 inhibitors?

Answer 29

Evolocumab, many PCSK9 inhibitors are humanized monoclonal antibodies

Question 30

What enzyme hydrolyzes triglycerides in the periphery to free fatty acids and where is this located?

Answer 30

LPL, inside of the lumen of capillaries

Question 31

Severe hyperlipidemia usually above 1000 mg/dL can cause what acute condition?

Answer 31

Acute pancreatitis

Question 32

What are examples of fibrates

Answer 32

Gemfibrozil and fenofibrate

Question 33

MOA of fibrates.What is the main effect of fibrates therapy in terms of LDL, VLDL, HDL and triglycerides.

Answer 33

Fibrates activate PPAR alpha to up regulate LDL receptors in extra hepatic tissues. The main effect of fibrates is to decrease serum triglycerides, as a result serum VLDL is decreased and hence LDL is decreased. Fibrates also increase HDL by directly increasing the production of lipoproteins A1 and A2.However the main effect of fibrates is to decrease serum triglycerides.

Question 34

What are the adverse effects of fibrates?

Answer 34

Increased risk of myopathy especially when combined with statins, they can cause cholesterol gall stones

Question 35

Explain the use and MOA of niacin

Answer 35

Niacin (Vitamin B3) is the most effective drug in increasing HDL, additionally it decreases VLDL, LDL and serum triglycerides by decreasing the secretion of VLDL from the liver. Niacin also decreases triglyceride release from adipose tissue.MOA is unknown

Question 36

What are the adverse effect of niacin?

Answer 36

Niacin can cause cutaneous flushing and warmth, this effect is mediated by prostaglandins. NSAIDs can be used to avoid this.Can cause hyperglycemia and hyperuricemia.Elevated liver function tests

Question 37

MOA of fish oil

Answer 37

High in omega 3 fatty acids, reduce serum triglycerides by decreasing production of apolipoprotein B and VLDL.

Question 38

Does fish oil help with mortality and morbidity in people with CV disease?

Answer 38

Absolutely.