Hyperlipidemia Flashcards Preview

Pharmacology > Hyperlipidemia > Flashcards

Flashcards in Hyperlipidemia Deck (37):
1

What is the function of LDL?

Carries cholesterol from liver to peripheral tissues (breakdown produce of VLDL, very low TG content and high cholesterol content).

Leftover LDL is uptaken by liver LDL-R.

2

What is the major apoprotein expressed on LDL, and what is its function?

Apo B-100, organizes the particle and acts as the ligand for LDL removal by binding LDL-R in liver

3

What does HDL do?

Mediates reverse cholesterol transport by uptaking excess cholesterol from the periphery, including macrophages / foam cells, transfers it to VLDL or back to liver (B1 scavenger receptor)

4

What is the primary mechanism by which LDL induces thrombo-embolism?

Oxidized-LDL accumlates in arterial wall, monocytes are recruited and become macrophages -> foam cells. Foam cells are lodged in arterial wall and cause stenosis, may burst and recruit more macrophages for oxidized-LDL uptake.

If the plaque ruptures, a clot may be formed on it, which can lodge in a coronary artery (MI) or brain (stroke)

5

What drug inhibits the dietary intake of cholesterol and how does it do this? Is it used alone?

Ezetimibe - inhibits intestinal cholesterol transporter (NPC1L1) - typically used in combination with statins (monotherapy shows minimal cholesterol reduction)

6

What other pathways will be affected via statin use?

1. Protein lipidation
2. Coenzyme-Q formation -> underlies myopathy of statins
3. Steroid hormones, vitamin D, bile acids

7

How does LDL-R endocytosis work and when is it upregulated?

Clathrin-mediated endocytosis once the ligand binds

Low cholesterol levels in the liver needed for bile acid synthesis and membrane maintenance signals upregulation of LDL-R and a further reduction in circulating LDL (key mechanism of cholesterol meds).

8

What are the two most common forms of familial hypercholesterolemia?

1. Mutated LDL-R (endocytosis does not work properly)
2. Mutated and upregulated PCSK9 - protease which binds LDL-R and induces its endocytosis and lysosomal degradation independent of LDL binding. -> lack of LDL-R will increase LDL and heart attack risk

9

What are the two PCSK9 inhibitors and who uses them? How do they work?

1. Alirocumab
2. Evolucumab

Used as a second line to statins when LDL remains high or statin side effects are high, but very expensive.

Increases the expression of LDL-R on liver by monoclonally binding PCSK9

10

How do statins work? Where do they act?

Competitive inhibition of HMG-CoA reductase, which converts HMG-CoA into mevalonate.

Act primarily in the liver, which is the major site of cholesterol storage and synthesis

11

What is the primary way in which statins reduce LDL-C? What does this have to do with effectiveness in familial hypercholesterolemia?

Lowered intracellular cholesterol levels lead to upregulation of LDL-R transcription, increasing LDL endocytosis

-> familial hypercholesterolemia -> LDL-R gene is mutated so there is only a minor LDL-reduction

12

Which two statins have the longest half-life?

Atorvastatin and rosuvastatin -> 20 hours, only need to be taking once daily. (Lipitor and crestor)

13

What effect do statins have on triglycerides and why?

Large reduction, often 30-50%, due to decreased VLDL production from lack of cholesterol, and scavenging of VLDL from LDL-receptor (since it also expresses Apo-B100)

14

What is the most common statin side effect and sub-side effect?

Myopathy - potentially due to inhibition of Co-Q10 synthesis.

Rhabdomyolysis may occur - fatal statin toxicity leading to induced muscle breakdown (Autoimmune) -> may lead to kidney failure

15

What metabolic syndrome do statins put you at risk for?

Type 2 diabetes, although CV risk reduction outweighs this

16

Why do people think statins cause memory loss?

Cholesterol is an important part of neuronal membranes

17

What are the statins metabolized via CYP3A4 and what drugs can make this a problem?

Simvastatin, lovastatin, and atorvastatin

Macrolides, azole antifungals, and HIV protease inhibitors may decrease their metabolize and increase risk of myopathy / rhabdomyolysis

18

What drug commonly increases plasma levels of statins and what can be taken instead?

Gemfibrizol, a fibrate to lower triglycerides

Can take fenofibrate instead

19

When are statin combination therapies used?

Patients seeing insufficient LDL-C lowering with statins alone, or who are unable to take high doses of statins due to side effects (myopathy)

20

When are statins + niacin given?

High LDL-C and low HDL-C levels

21

When are statins + fenofibrate given?

High triglycerides + high LDL-C

22

What are the risk factors for coronary heart disease?

1. Diabetes
2. Age (males over 45 or females over 55)
3. Gender - males at higher risk
4. Dyslipidemia
5. Family history of CHD
6. Hypertension
7. Current smoker
8. Obesity
9. Sedentary lifestyle

23

What is primary vs secondary prevention of CHD?

Primary prevention = prevention before any cardiac event (i.e. MI or stroke)

Secondary prevention = prevention (i.e. statin use) following a cardiac event

24

What is the high vs low total cholesterol range?

Low / desirable: <200 mg/dL
High: >240 mg/dL

25

What is the low vs high HDL cholesterol range?

Low: <40 mg/dL
High (goal): >60 mg/dL

26

What is low vs high LDL?

Low (good): <100 mg/dL
High: >160, >190 is very high

27

What are normal vs high TG levels?

Normal: <150 mg/dL
High: >200, can be in the thousands

28

How well does a reduction in LDL-C correlate with cardiac risk?

A 40 mg/dL drop translates to a 20% reduction in 10 year MI / stroke risk

29

How do bile acid sequestrants work?

50% of daily cholesterol synthesis is used for bile acid synthesis.

These are insoluble, gel-like substances which reside in intestine and bind to bile acids, are eventually eliminated in feces -> more cholesterol diverted to bile acid synthesis, more LDL-R scavenging of LDL is needed

30

What are the bile acid sequestrants and are they used as a monotherapy?

Cholestyramine and colestipol

Not given as monotherapy -> biosynthesis would be unrepgulated. Work well in combination with statins

31

What are the effects of major niacin supplementation?

Reduced LDL, increased HDL, reduced triglyerides

32

What is the mechanism of action of niacin?

Binds to and activates GPCR in adipose tissue, decreasing release of free fatty acids from stored triglycerides, reducing need for VLDL packaging by liver, and reduction in LDL.

HDL is increased by improved stability of Apoprotein A1

33

Is niacin used as a monotherapy, and what are its adverse effects?

Typically used with statins, especially when HDL levels are low

Main side effect: Extreme flushing and itching (turn bright red), and you have to eat a lot of it. Must take NSAIDs to reduce flushing.

34

What are the two fibrates typically used?

gemfibrozil (may have interaction with statins)
fenofibrate

35

What is the mechanism of action of fibrates?

Activates PPARalpha -> ligand activated steroid receptor, lowers release of VLDL in liver and upregulates lipoprotein lipase to decrease tags

Reduces triglyceride levels, minimal effects of HDL/LDl

36

Why do we care about lowering triglyceride levels?

High TGs (>500 mg/dL) are associated with increased risk of pancreatitis, part of metabolic syndrome

37

What is metabolic syndrome?

Central obesity, insulin resistance, high blood pressure, and fatty liver (presence of multiple risk factors together)