Dyslipidemia

Question 1

What is the leading cause of death in the US?

Answer 1

Atherosclerosis (specifically CAD)

Question 2

What is the basic process by which plaque forms?

Answer 2

1. LDL brings cholesterol into the cell
2. LDL is oxidized by reactive oxygen species (ROS)
3. oLDL (oxidized LDL) is taken up by a macrophage & cholesterol is absorbed into macrophage forming a “foam cell”.
4. Foam cell bursting & the resulting deposition of cholesterol forms the basis for plaque formation.

Question 3

What are the two main lipids associated with CAD?

Answer 3

• Cholesterol
• Triglycerides

Question 4

What lipid forms fat tissue/buildup & is the basis for metabolic syndrome?

Answer 4

Triglycerides

Question 5

Blood levels of cholesterol are considered high at _______ mg/dL.

Answer 5

200

Question 6

How long would it take to lower cholesterol, without a statin, through diet & lifestyle changes alone?

Answer 6

3-5 years

Question 7

What is the synthesis pathway for cholesterol?

Answer 7

Acetyl-CoA → HMG-CoA → HMG CoA-reductase → Mevalonate → Cholesterol

Question 8

What is the rate-limiting step in the cholesterol synthesis pathway?
Where do statin’s inhibit cholesterol formation?

Answer 8

• Mevalonate
• HMG-CoA reductase

Question 9

What is the largest high-fat/low-protein lipoprotein?
Where are these made?
What do they carry?
Where are they degraded? What should be known about their degraded products?

Answer 9

• Chylomicrons
• GI tract.
• Carry triglycerides & cholesterol
• Degraded by cells, then liver; remnants are pro-atherogenic.

Question 10

VLDLs are secreted by what?
What are they converted to? How?

Answer 10

• Liver
• VLDLs are converted to IDLs & LDLs via the endogenous pathway.

Question 11

An excess of LDLs results in an excess of cholesterol in the ________.
How do HDLs differ from this?

Answer 11

• Arteries
• HDLs “scavenge” cholesterol from the arteries. ↓ HDLs are associated with atherosclerosis.

Question 12

How are VLDL’s calculated?
How about LDL’s?

Answer 12

VLDL = Triglycerides/5
LDL = Total cholesterol - VLDL - HDL

Question 13

What would a normal LDL/HDL ratio be?
What ratio would half one’s risk of CAD?
What ratio would double ones risk of CAD?

Answer 13

3 to 3.5
1 to 1.5
5 to 6

Question 14

What two factors can invalidate a measure LDL/HDL ratio?

Answer 14

• Triglycerides greater than 400mg/dL
• Chylomicrons present in sample

Question 15

What would a normal HDL level be in someone?

Answer 15

around 45 mg/dL

Question 16

Familial hypercholesterolemia involves increases levels of what?

Answer 16

LDLs

Question 17

What two conditions, highlighted in lecture, result in hypertriglyceridemia?

Answer 17

• Diabetes Mellitus
• EtOH abuse (↑ NADH)

Question 18

What three dietary intakes can be used to decrease risk of atherosclerosis? Give the reasoning why for each example.

Answer 18

• ↓ cholesterol
• ↓ fat, alcohol, & excess calories =↓ triglycerides
• ↓ sucrose/fructose = ↓ VLDLs

Question 19

What other dietary measures can be utilized to help decrease risk of atherosclerosis?

Answer 19

• 20% of calories from fat
• ↑ fiber
• weight reduction
• ↑ intake of Ω-3 fatty acids.

Question 20

What is the most important hyperlipidemia medication?
What is the primary result of these drugs?
When are they prescribed?

Answer 20

• Statins (HMG-CoA reducase inhibitors)
• ↓ LDL & cholesterol levels
• Prescribed with CAD symptoms regards of lipidemia.

Question 21

What are the 4 facets of a statin’s mechanism of action?

Answer 21

1. ↓ cholesterol synthesis
2. ↑ LDL reuptake (scavenged from liver)
3. modest ↓ in triglycerides
4. small ↑ in HDL

Question 22

When are statins typically administered? Why?
What is the dosing for pregnant & lactating women.

Answer 22

• With food and/or at bedtime (cholesterol synthesis occurs at night.)
• Not given to pregnant/lactating women.

Question 23

What are the two adverse outcomes of statin toxicity?

Answer 23

1. ↑ liver enzymes (especially if patient is of asian descent)
2. ↑ CK & muscle pain or weakness (typically minor but can be major)

Question 24

How does Niacin (Vitamin B₃) treat dyslipidemia?

Answer 24

Reduction of VLDL secretion from liver = ↓ VLDL/LDL & ↑ HDL.

Question 25

What does Niacin toxicity cause?

Answer 25

• Cutaneous vasodilation (flushing)
• ↑ liver enzymes

Question 26

How do Fibrates treat HLD?

Answer 26

↑ lipolysis in the liver

Question 27

How do Bile-acid binding resins work?
What is the prototypical drug of this class?
When are they given?
What can occur with other orally administered drugs if given with these?

Answer 27

• BABRs bind to bile acids & prevent reabsorption of food.
• Colesevalam HCl
• Given with meals.
• Decreased absorption of other PO drugs.

Question 28

How does Ezetimibe work?

Answer 28

Inhibition of sterol absorption in the intestine by blocking cholesterol transport.

Question 29

What is the one-sentence MOA of PCSK9 Inhibitors?

Answer 29

Prevention of LDL receptor from being recycled by inhibiting the PCSK9 molecule from tagging the receptor for destruction.

Question 30

What molecule targets an LDL receptor for destruction instead of recycling?

Answer 30

PCSK9

Question 31

PCSK9 Inhibitors with statins lower LDL levels by ______.

Answer 31

65%

Question 32

Gemfibrozil (lopid)

Answer 32

decreases VLDL
modest decrease in LDL
toxicity - rate (GI upset)
increases lipolysis in liver (PPAR)

Question 33

Evolocumab (Repatha)

Answer 33

LOWERED LDL 65%

mild allergy side effect (nasopharyngitis)

monoclonal antibodies - binds PCSK9, inhibit

injection 1x/2 weeks