Crr Week 5: Dyslipidemia Drugs (Blair)

Front 1

What are the most effective drugs in treating dylipidemias?

Back 1

Statins

Front 2

What is the MOA of statins?

Back 2

Competitively inhibit the rate limiting ezyme in cholesterol biosynthesis, HMG-CoA reductase, thereby reducing synthesis of cholesterol

Front 3

What is the function of pancreatic lipase?
Which cofactor is required for its function?

Back 3

It requires colipase
Binds to the emulsified droplets and metabolizes triglyceridese into monoglycerides and fatty acids.

Front 4

What are micelles composed of?

Back 4

Monoglycerides, fatty acids, phospholipids, and bile salts

Front 5

Which enzyme digests cholesteryl esters?
What are the products?

Back 5

Cholesteryl ester hydrolase
Products: cholesterol and fatty acids

Front 6

Cholesterol interacts with which receptor protein for absorption?

Back 6

Niemann-Pick C1-like 1 protein (NPC1L1)

Front 7

Where are apoproteins synthesized?

Once made, where do they move?

Back 7

Rough endoplasmic reticulum (RER)

*Move to the smooth ER

Front 8

What are the largest plasma lipoproteins?

Back 8

Chylomicrons
(they are also the least dense-- 98-99% lipid)

Front 9

What are the chylomicrons made up of?

Back 9

1. Triglycerides (85%)
2. Apoproteins
3. Phospholipids
4. Cholestyryl esters

Front 10

Why are blood lipid levels only tested after a 12 hour fast?

Back 10

Because you don't want chylomicrons to distort the blood lipid levels
(chylomicrons are present in plasma for 3-6 hours, and are not completely gone for 12 hours)

Front 11

How are chylomicrons metabolized?

Back 11

As they travel through circulations, tissues that synthesize lipoprotein lipase partially metabolize them

Tissues:
1. Skeletal/ cardiac muscle
2. Adipose tissue
3. Breast tissue of lactating women

Front 12

What does lipoprotein lipase digest and what are the products?

Back 12

Chylomicrons

1. Free fatty acids
2. Glycerol

(Remaining portions of chylomicrons are called chylomicron remnants)

Front 13

Which apoprotein component is trasnferred onto chylomicrons, and what is the function of this?

Back 13

ApoE (transferred from HDLs)

*This component binds to receptors on hepatocytes, allowing the liver to remove chylomicron remnants from the blood

Front 14

Which two receptors bind ApoE components on chylomicrons?

Back 14

1. Low density lipoprotein receptors (LDLR)
2. LDL receptor-related protein (LRP)

Front 15

What sort of process allows hepatocytes to absorb chylomicron remnants?

Back 15

Receptor-mediated endocytosis
(accomplished by ApoE binding to LDLR and LRPs)

Front 16

What sort of transfer process allows absorption of long chain fatty acids and triglycerides into the intestinal epithelial cells?

Back 16

Diffusion

Front 17

What happens to the monoglycerides and fatty acids that are absorbed into the intestinal epithelial cells?

Back 17

They are reformed into triglycerides
(this maintains diffusion gradient for more free acids and monoglycerides to be absorbed)

*The triglycerides are then moved to the SER

Front 18

Which enzyme reesterifies cholesterol that is absorbed into intestinal epithelial cells?

Back 18

Acyl coenzyme A: cholesterol acyltransferase (ACAT)

*This maintains absorption gradient for cholesterol absorption

*The resultant cholesterol esters are moved to the SER

Front 19

What happens once cholesterol esters and triglycerides are moved to the SER?

Back 19

SER packages them into nascent (precursor) chylomicrons, which then move to the Golgi apparatus.

Front 20

What happens to chylomicrons once they are created?

Back 20

They leave the small intestinal epithelial cell by exocytosis.

*They are too large to enter capillaries, so they are taken up by the lacteals and enter the bloodstream via the thoracic duct

Front 21

Within chylomicrons, are there more triglycerides or more cholesteryl esters?

Back 21

Triglycerides make up the majority of chylomicrons
(TG : CE ration is 10)

Front 22

How do hepatocytes regulate cholesterol levels in the body?

Back 22

By controlling its synthesis
(based on the levels of cholesterol in the hepatocytes)

Front 23

What is the rate-limiting step of cholesterol synthesis?

Back 23

HMG-CoA reductase
*converts 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate

Front 24

What is the primary way the liver gets rid of excess cholesterol?

Back 24

Cholesterol is converted to bile salts and enters the enterohepatic circulation

Front 25

What are VLDLs composed of, and where are they made?

Back 25

1. Cholesterol
2. Cholesteryl esters
3. apoB-100
4. TGs
5. Phospholipids

*Synthesized in the liver and secreted by exocytosis into the blood stream

Front 26

How are VLDLs metabolized?

Back 26

They are partially metabolized in the blood stream (like chylomicrons) by lipoprotein lipase into monoglycerides and free fatty acids which are taken up by the tissues

*Produces VLDL remnants --> Intermediate-density lipoproteins

Front 27

VLDL remnants are also termed what?

Back 27

Intermediate-density lipoproteins (IDLs)

Front 28

What are the 2 major fates of IDLs?

Back 28

1. Can be recycled into the liver
2. Can interact with hepatic lipase

Front 29

Describe how IDLs interact with hepatic lipase?

Back 29

Hepatic lipase partially digests IDLs, releasing monoglycerides and fatty acids that are then taken up by the liver.

ApoE is removed

*The resulting lipoproteins are termed low-density lipoproteins (LDLs)

Front 30

What are the 2 major fates of LDLs?

Back 30

1. Recycled into the liver
2. Taken up by cells in the other body tissues.

Front 31

The apoB-100 can only bind to which receptor?

Back 31

LDLR

Front 32

Nascent HDLs are created by which organs?

Back 32

1. Liver
2. Small intestines

Front 33

What is the major apoprotein in HDLs?

Back 33

apoA-1

Front 34

Cholesterol that is floating around in blood can be esterified by an enzyme contained in HDLs-- what is this enzyme?

Back 34

Lecithin-cholesterol acyltransferase (LCAT)

*HDLs incorporate resultant CEs into their centers

Front 35

The liver delivers TGs and cholesterol to other tissues in the form of...?

Back 35

VLDLs

Front 36

What is the function of HDLs?

Back 36

Take up excess cholesterol from tissues and transfer it to VLDLs, IDLs, chylomicrons, and the liver.

Front 37

How is the synthesis of LDLR regulated?

Back 37

High cholesterol levels in the liver downregulate its synthesis

Front 38

How is HMG-CoA reductase regulated?

Back 38

By cholesterol levels in hapatocytes-- classic negative feedback

Front 39

How much cholesterol is excreted each day in stools, and what in what forms?

Back 39

1g of cholesterol

1/2 in form of bile acids
1/2 in form of reduced cholesterol, coprosterol

Front 40

How much cholesterol is absorbed from meals?
Consequently, how much cholesterol must be synthesized by the liver?

Back 40

0.2 g is absorbed from meals

0.8 g must be synthesized by the liver to make up for the extreted cholesterol

Front 41

What are the major lipid components of plaques?

Back 41

Cholesterol and its esters

Front 42

What are the major carriers of cholesterol in the blood?

Back 42

LDLs

Front 43

What is the current recommendation for total cholesterol level?

Back 43

<200 mg/dl

Front 44

What is the current recommendation for LDL-C levels?

Back 44

<130 mg/dl

Front 45

What is the current recommendation for HDL-C levels?

Back 45

>40 mg/dl for MEN
>50 mg/dl for WOMEN

Front 46

What is the current recommendation for the ratio of total cholesterol to HDL-C?

Back 46

5:1

Front 47

What is the current recommendation for the ratio of LDL-C to HDL-C?

Back 47

3:1

Front 48

What is the optimal level of LDL-C?

Back 48

<100 mg/dl

Front 49

Which range of total cholesterol levels is defined as "borderline to high"?

Back 49

200-239 mg/dl

Front 50

Which range of total cholesterol levels is defined as "high"?

Back 50

>240 mg/dl

Front 51

Which range of LDL-C is defined as "borderline to high"?

Back 51

130-159 mg/dl

Front 52

Which range of LDL-C is defined as "high"?

Back 52

>160 mg/dl

Front 53

Triglycerides should be less than what value for the desirable range?

Back 53

<120 mg/dl

Front 54

Which levels of TGs are defines as "borderline to high?'

How about "high"?

Back 54

120 - 199 mg/dl --> borderline to high

>200 mg/dl --> HIGH

Front 55

What condition can be caused by TG levels above 1000 mg/dl?

Back 55

Pancreatitis
*Major problem with high TGs

Front 56

What are xanthomas?

Back 56

Tumor masses of lipids contained in foam cells

*Associated with plasma levels greater than 300 mg/dl

Front 57

What is the problem behind primary chylomicronemia?

Back 57

Deficiency of lipoprotein lipase
*Chylomicrons cannot be metabolized

Leads to SEVERE LIPEMIA (2000-3000 mg/dl of TGs)

Front 58

Which disease may not be discovered until a patient has an acute attack of pancreatitis?

Back 58

Primary chilomicronemia

Front 59

Is primary chylomicronemia autosomal dominant or recessive?

Back 59

Recessive

Front 60

Which disease results from a failure to adequately remove triglyceride-rich lipoproteins?

Back 60

Familial hypertriglyceridemia

Front 61

Which condition leads to increased levels of VLDL, LDL, or both?

Back 61

Familial combined hyperliporoteinemia

Front 62

Are xanthomas typically present in familial combined hyperlipoproteinemia?

Back 62

No

Front 63

Are xanthomas typically present in familial hypertriglyeridemia?

Back 63

Yes

Front 64

Are xanthomas generally present in primary chylomicronemia?

Back 64

Yes

Front 65

Which condiition results from a defect in apoE synthesis?

Back 65

Familial dysbetalipoproteinemia

Front 66

What is the problem behind familial hypercholesterolemia?

Back 66

Mutations in the LDL receptor, which prevents cholesterol uptake into the liver

Front 67

Is Familial hypercholesterolemia autosomal dominant or recessive?

Back 67

Dominant

Front 68

Describe the different total cholesterol levels of those who are heterozygous and those who are homozygous for Familial hypercholesterolemia

Back 68

Heterozygous --> 250- 500 mg/dl
Homozygous --> above 1000 mg/dl

*Total cholesterol should be <200 mg/dl

Front 69

What sort of trigylceride levels are present in people with Familial hypercholesterolemia?

Back 69

Normal

Front 70

Which condition results from damaged ApoB-100?

Back 70

Familial ligand-defective apolipoprotein B

*Impairs binding of LDLs to hepatocytes and other cells, so plasma LDLs increase.

Front 71

What is the significance of liporotein(a)?

Back 71

It is found in atherosclerotic plaques and is associated with higher risk coronary artery disease

Front 72

What is the result of HDL deficiency?

Back 72

Increased atherosclerosis

Front 73

Which genetic disorders are associated with HDL deficiency?

Back 73

1. Tangier disease
2. LCAT deficiency
3. Familial hypoalphalipoproteinemia

Front 74

Which conditions can lead to both hypertriglyceridemia and hypercholesterolemia?

Back 74

1. Excess corticosteroids
2. Hypopituitarism

Front 75

Does diabetes mellitus lead to hypertriglyceridemia or hypercholesterolemia?

Back 75

Hypertriglyceridemia

Front 76

Does alcoholism lead to hypertriglyceridemia or hypercholesterolemia?

Back 76

Hypertriglyceridemia

Front 77

Does anorexia nervosa lead to hypertriglyceridemia or hypercholesterolemia?

Back 77

Hypercholesterolemia

Front 78

Does hypothyroidism lead to hypertriglyceridemia or hypercholesterolemia?

Back 78

Hypercholesterolemia

Front 79

Does obesity lead to hypertriglyceridemia or hypercholesterolemia?

Back 79

Hypertriglyceridemia

Front 80

What are the main dietary components that increase LDL?

Back 80

1. Cholesterol
2. Saturated fats
3. trans-fats

Front 81

What are the main dietary components that increase triglycerides?

Back 81

1. Total fat
2. Alcohol
3. Excess calories

Front 82

Dietary fat intake should be limited to what percentage of daily caloric intake?

Back 82

20 - 25% of daily caloric intake
(Saturated fats no more than 8%)

Front 83

What type of fat is recommended for reducing blood lipid levels?

Back 83

cis-monosaturated fats

Front 84

People with high VLDL and IDL should especially be aware of what sort of dietary limitations?

Back 84

1. Avoid alcohol
2. Restrict caloric intake

Front 85

How do statin drugs affect the regulation of LDLR and what is the result?

Back 85

Statin drugs decrease the synthesis of cholesterol, which upregulates LDLRs.
*This results in increased uptake of LDLs into the liver, decreasing plasma LDLs

Front 86

What is the effect of statins on LDL, VLDL, IDL, triglyceride, and HDL levels?

Back 86

Decreases ---> LDL, VLDL, IDL

At high doses, can decrease triglyceride levels

May increase HDL

Front 87

List 3 statin drugs approved for use.

Back 87

1. Lovastatin
2. Simvastatin
3. Pravastatin

Front 88

What is the prototype statin?

Back 88

Lovastatin

Front 89

How is Pravastatin unique?

Back 89

It is metabolized differently than the other statins
So if a patient has trouble tolerating the others, this may be a useful alternative.

Front 90

List 5 cardioprotective effects of statin drugs.

Back 90

1. Improves endothelial function (facilitates NO production)
2. Enhance stability of plaques
3. Reduce inflammation
4. Reduce oxidation of lipids in vascular wall
5. Reduce platelet aggregation

Front 91

What are 2 adverse effects of statins?

Back 91

1. Myopathy
2. Rhabdomyolysis

Front 92

Conditions that increase plasma levels of statins can lead to ______.

Back 92

Myopathy

Front 93

Which drug blocks uptake of statins into the liver, increasing plasma levels of statins?

Back 93

Gemfibrozil

Front 94

What are the safest antilipidemic drugs?

Back 94

Bile acid resins
(they are not absorbed from the GI tract)

Front 95

What is the MOA of bile acid resins?

Back 95

They are (+) charged and bind to (-) charged bile acids, inhibiting bile acid reabsorption.

*Results in increased bile acid synthesis, reducing the amount of cholesterol in the liver

Front 96

What is the effect of bile acid resins on HMG-CoA reductase and LDLR synthesis?

Back 96

Both are increased

Increased LDLR synthesis decreases plasma LDL, but this is curbed a bit by the increased cholesterol production

Front 97

How can the effectiveness of bile acid resins be improved?

Back 97

By pairing them with a statin
(this will reduce production of cholesterol)

Front 98

What is the MOA of Niacin? (4)

Back 98

1. Inhibits lipolysis of triglycerides in adipose tissue
*Fewer free fatty acids are delivered to the liver

2. Inhibits synthesis and esterification of fatty acids in the liver
*Both effects prevent the liver from producing VLDLs, which reduces LDLs

3. Increases the activity of lipoprotein lipase

4. Reduces clearance of apoA-I (increases HDLs)

Front 99

Why should Niacin not be used in most patients?

Back 99

Serious adverse effect: HEPATOTOXICITY

*2g of Niacin is commonly needed to produce therapeutic effect; however, this dose of Niacin makes patients particular susceptbile to liver failure

Front 100

Which drug blocks cholesterol absorption by interfering with the NPC1L1 transport protein?

Back 100

Ezetimibe

Front 101

How is the effectiveness of Ezetimibe limited?

How can the effectiveness be increased?

Back 101

This drug blocks the intestinal absorption of dietary cholesterol, which leads to increased endogenous production of cholesterol

*Often paired with a statin to increase effectiveness

Front 102

What do fibrate derivatives activate?

Back 102

PPAR transcription factors
(peroxisome proliferator activated receptors)

Front 103

List one drug in the class of fibrate derivatives.

Back 103

Clofibrate

Front 104

What is the MOA of Clofibrate?

Back 104

Activation of PPAR, which facilitates fatty acid oxidation and synthesis of LPL are facilitated.

*Reduction of triglycerides in plasma

Front 105

Which group of drugs are the first choice for treating severe triglyceridemia?

Back 105

Fibrates
(Clofibrate)

Front 106

The combination of which 2 drugs can lead to myopathy and rhabdomyolysis?

Back 106

1. Fibrates (esp. Gemfibrozil)
2. Statins

Front 107

Give one example of a bile acid resin.

Back 107

Cholestyramine

Front 108

Diet alone cannot adequately treat which 2 conditions?

Back 108

1. Familial hypercholesterolemia
2. Familial combined hyperlipidemia

Front 109

What kind of factors may increase the plasma levels of statins?

Back 109

1. * Hepatic or renal dysfunction/ disease
2. Age
3. Diabetes
4. Small body
5. Hypothyroidism