Lipid Disorders

Question 1

Cholesterol is primarily derived from what?

Answer 1

LDL’s

Question 2

What is atherosclerosis?

Answer 2

• abnormal deposition of cholesterol in the arteries

Question 3

VLDL’s are the endogenous forms of ____

Answer 3

cholesterols

Question 4

Describe triglycerides?

Answer 4

• primarily chylomicrons, VLDLs as well

- increase pancreatitis

Question 5

What are some of the other key factors in deposition on artery walls?

Answer 5

• smoking
• hypertension
• diabetes
• genetic factors

Question 6

What is the LDL involvement in the generation of atherosclerosis?

Answer 6

• LDL’s make their way inside the artery, and from here are able to produce oxidizing products (are able to oxidize)
• from here, they cannot move out of the artery, have to stay here inside the artery
• they send out signals to attract monocytes into the intima
• monocytes are transformed into macrophages and are very efficient into taking up LDL
• increase in the level of foam cells, where cholesterol can be taken up- these foam cells developing a core that allows plaques to form on the artery wall, and these plaques can get so big that they can cause blockage

Question 7

What is the action of HDL?

Answer 7

• takes cholesterol from the peripheral circulation and takes them back into the proteins that of to the liver
• allows the cholesterol from being excreted into the bile from the liver
• HDL cannot cause the build up of the plaque- it can go into the lymphatic vessels because it is so small, but because LDL is so big it cannot move from inside the arteries to the lymph vessels

Question 8

What would be recommend to a patient that has no risk factors and has only slightly elevated cholesterol?

Answer 8

• no medication intervention , do NOT give drugs

Question 9

What are the potential sites to decrease cholesterol?

Answer 9

1. decreasing GI uptake
   - decreasing dietary intake
   - decreasing reabsorption of bile acids
   - decreasing reabsorption of cholesterol
2. decreasing LDL levels
   - decreasing VLDL
   - increasing LDL receptors
3. decreasing endogenous cholesterol synthesis

Question 10

What are the non-pharmacological treatment options for lowering cholesterol?

Answer 10

• can increase dietary fibre

- adding in omega 3 fatty acids- will use a reduction in LDL cholesterol levels

Question 11

What are HMG-CoA reductase inhibitors also known as?

Answer 11

statins

Question 12

Statins are known as the first choice for most patients with a risk for what?

Answer 12

coronary heart disease

Question 13

What do statins do?

Answer 13

• decrease LDL levels
• also decrease triglyceride levels
• patients with a coronary artery disease - decreased cardiac morbidity, mortality, reduced incidence of stroke
• benefits seen with initial high or normal cholesterol

Question 14

What is the mechanism of statins?

Answer 14

• inhibit HMG-CoA reductase, the rate limiting step of cholesterol synthesis
• compensatory increase in LDL receptors
• best if given in the evening- diurnal pattern of cholesterol synthesis

Question 15

What are the adverse effects of statins?

Answer 15

• well tolerate but contraindicated in pregnancy
• myalgia, muscle weakness
• may increase with cyclosporin, fibrates or niacin
• monitor creatine kinase levels
• increase in plasma aminotransferase >3x in ,2% (symptomatic hepatitis is rare)
• first pass metabolism- CYP3A4 (avoid inhibitors like grapefruits with some statins)
• renal dysfunciton, behavioural and cognitive, diabetes, neuropathy

Question 16

What is the effect that grapefruit will have on the availability of stains in the body?

Answer 16

there is an INHIBITION of the enzyme (CYP3A4) that metabolizes statins, causing an increase in the amount go medication that is in the body
- the concentration of the statin is increased

Question 17

Which statins in particular are affected by grapefruit juice?

Answer 17

• atorvastatin and simvastatin

Question 18

Ezetimibe belongs to what class?

Answer 18

cholesterol absorption inhibitors

Question 19

Ezetimibe causes inhibition of both ___ and ____ cholesterol absorption

Answer 19

dietary and biliary

work at the intestinal brush border

Question 20

What is the specific protein that ezetimibe works on?

Answer 20

• it inhibits a cholesterol transport protein that is known as NPC1L1

Question 21

Ezetimibe lowers cholesterol by _____ when used alone, but you can get reflex increase in cholesterol ____

Answer 21

15-20%

- synthesis

Question 22

What is the one dangerous part of potentially combining ezetimibe with a statin?

Answer 22

possible greater elevations of transaminases compared to just using statins alone (does allow a lower dose of statin to be used however)

Question 23

What are the adverse effects associated with using ezetimibe?

Answer 23

• myalgia, hepatitis, rhabdomyolysis, acute pancreatitis

Question 24

What are the examines of bile acid binding resins?

Answer 24

• cholestyramine (Questran), colestipol (Colestid), colesevelum

Question 25

What are tile acid binding resins useful for?

Answer 25

- useful in mild to moderate elevated LDL levels | - effective with statins or nicotinic acid in high LDL levels

Question 26

Are bile acid binding resins absorbed by the gut?

Answer 26

- no, they are not (they are anion exchange resins)

Question 27

What is the mechanism of action of bile acid binding resins?

Answer 27

- binds bile acids in the intestinal lumen - prevents reabsorption (normally 95% reabsorbed) - to produce new bile acids, the liver must do what? - > take up cholesterol (increase LDL receptors and/or synthesize de novo cholesterol)

Question 28

What are the most common adverse effects associated with bile acid binding resins?

Answer 28

- may increase LDL levels - decrease absorption of fat soluble vitamins (vitamin K deficiency is a problem) - nausea, constipation and bloating - unpleasant taste and texture - absorption of drugs is altered (positive, negative and neutral) eg. digitalis, thiazides, warfarin and aspirin

Question 29

Why is ezetimibe beneficial to use with a statin?

Answer 29

- additively lower the level of cholesterol - ezetimibe decreases cholesterol uptake in the gut, but compensatory increase in cholesterol synthesis in the liver - HMG-CoA reductase inhibitors blocks the increased synthesis in the liver

Question 30

What are some of the reasons that there is such a failure to achieve the LDL target concentrations?

Answer 30

- poor adherence to the treatment - high baseline LDL-concentrations - high cholesterol diet - high cholesterol absorption - variable statin release - inability to tolerate (higher dose) statins

Question 31

What are the newest therapies used to lower lipids?

Answer 31

- targeting the LDL receptor for degradation - inject human monoclonal antibodies to PCSK9 to increase LDL receptors on the liver - known as evolocumab

Question 32

What is the role o PCSK9 in the regulation of LDL receptor expression

Answer 32

- LDL particle binds to the LDL receptor in the absence of the PCSKp complex - LDL receptor recirculates back to the surface - more LDL receptor on the surface of the liver which will allow the liver to pull in more of the LDL and metabolize it - this receptor is primarily found on the liver, BUT you can still see muscle weakness with this therapy

Question 33

What are the potential sites to decrease triglycerides?

Answer 33

- decrease dietary triglycerides - increase lipoprotein lipase activity - decrease VLDL secretion from the liver

Question 34

What is the non-pharmacological approach in decreasing lipids?

Answer 34

- decreasing dietary TG's | - increasing dietary fibre - increasing soluble and insoluble fibre

Question 35

What are the other uses of dietary fibre?

Answer 35

- increases bulk of the stool - good for constipation - decreases colonic cancer

Question 36

In fenofibrate and gemfibrozil (fibrates) the incidence of death from coronary heart disease, non-fatal MI and stroke was decreased, but what was NOT altered?

Answer 36

- LDL levels were unaltered

Question 37

Vibrates may ____ triglycerides and may _____ HDL

Answer 37

decrease | increase

Question 38

What is the mechanism of fibrate action?

Answer 38

- increased VLDL clearance (increase lipoprotein lipase activity) - decreased VLDL secretion

Question 39

What are the adverse effects of fibrates?

Answer 39

- flu-like: muscle cramps, tenderness, stiff, weak - - increased myopathy when combined with statins - avoid in hepatic or renal dysfunction - may potentiate oral anticoagulants and hypoglycaemia agents - increases cyclosporine clearance - transplant rejection? - use with caution if increased risk of biliary tract disease (women, obese patients, First Nation)

Question 40

Generally describe niacin?

Answer 40

- water soluble vitamin B3 (nicotinic acid) - NOT nicotinamide - low dose can increase HDL levels (most effective) - higher dose - decreases VLDL levels - decreases triglycerides and may therefore may decrease LDL levels

Question 41

What effect does niacin have on men with a previous MI?

Answer 41

- decreases the incidence of a non-fatal MI and at 9 years a decreases mortality rate

Question 42

What is the mechanism that nicotinic acid has action at?

Answer 42

- decreased hepatic VLDL production - activated Niacin receptors in adipocytes -> decrease in cAMP -> decreases TG hydrolysis -> less fatty acid in circulation to be taken up by the liver and converted to TG and then secreted as VLDL - increased VLDL clearance (increase lipoprotein lipase activity) - effective at decreasing triglycerides and increasing high density lipoproteins

Question 43

What are the common adverse effects of niacin use?

Answer 43

- limited because it is poorly tolerated - skin flushing and pruritus (acute and aspirin blunts) - exacerbation of peptic ulcers - may increase aminotransferase or alkaline phosphatase (monitor liver function regularly for hepatotoxicity) - can lead to glucose intolerance