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Cardiovascular > Medical Pharm: Pathophysiology and Treatment of Hyperlipidemia (Elam) > Flashcards

Medical Pharm: Pathophysiology and Treatment of Hyperlipidemia (Elam) Flashcards

1
Q

ApoA-I has a primary source:
Lipoprotein association:
Function:

A

Source: Intestine, liver
Lipoprotein association: HDL, chylomicrons
Function: structural protein for HDL, activates LCAT

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2
Q

ApoA-II has a primary source:
Lipoprotein association:
Function:

A

Source: Liver
Association: HDL, chylomicrons
Function: Structural protein for HDL

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3
Q

ApoA-V has a primary source:
Lipoprotein association:
Function:

A

Source: liver
Association: VLDL ApoA-V is for VLDL, chylomicrons
Function: Promotes LPL-mediated triglyceride breakdown, release of FFA

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4
Q

Apo(a) has a primary source:
Lipoprotein association:
Function:

A

Source: liver
Association: Lp(a) (LDL)
Function: aberrant form of thromboplastin adheres to LDL (atherogenic)

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5
Q

ApoB-48 has a primary source:
Lipoprotein association:
Function:

A

Source: Intestine
Association: Chylomicrons
Function: Structural protein

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6
Q

ApoB-100 has a primary source:
Lipoprotein association:
Function:

A

Source: Liver
Association: VLDL, IDL, LDL, Lp(a) all bad stuff, in excess
Function: Structural protein

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7
Q

ApoC-II has a primary source:
Lipoprotein association:
Function:

A

Source: Liver
Association: Chylomicrons, VLDL, HDL
Function: Co-factor for LPL

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8
Q

ApoC-III has a primary source:
Lipoprotein association:
Function:

A

Source: Liver
Association: Chylomicrons, VLDL, HDL
Function: Inhibits lipoprotein binding to receptors

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9
Q

ApoE has a primary source:
Lipoprotein association:
Function:

A

Source: Liver
Association: Chylomicron remnants, IDL, HDL
Function: ligand for binding to LDL receptor

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10
Q

What is a desirable Total Cholesterol level?

What is considered high?

A

< 200 mg/dL desirable

> 240 mg/dL high

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11
Q

What is a desirable LDL cholesterol level?

What is considered high?

A

< 130 mg/dL desirable

> 160 mg/dL high

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12
Q

What is a desirable HDL cholesterol level?

What is considered high?

A

40 mg/dL for men, 50 mg/dL for women desirable

> 60 mg/dL high

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13
Q

What is a desirable triglyceride level?

What is considered high?

A

< 120 mg/dL desirable

> 200 mg/dL high

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14
Q

Regarding the primary hyperlipoproteinemias:
What is the defect present in primary chylomicronemia?
How does it manifest?

A

Defective removal of chylomicrons (apoC-II, LDL defect)

Manifestation: Chylomicrons, VLDL elevated, pancreatitis

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15
Q

Regarding the primary hyperlipoproteinemias:
What is the defect present in Familial hypertriglyceridemia?
How does it manifest?

A

Defective metabolism of VLDL (LPL defect)

Manifestation: VLDL elevated, hypertriglyceridemia, pancreatitis

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16
Q

Regarding the primary hyperlipoproteinemias:
What is the defect present in familial dysbetalipoproteinemia?
How does it manifest?

A

Defective metabolism of VLDL, chylomicrons, APoE defect (E2/E2 alleles).
Manifestation: VLDL and chylomicron remnants (IDL) elevated. Cholesterol and TG elevated 1:1. Atherosclerosis

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17
Q

Regarding the primary hyperlipoproteinemias:
What is the defect present in familial combined hyperlipidemia (FCH)?
How does it manifest?

A

Overproduction of ApoB (VLDL)

Manifestation: Variable phenotype, elevated VLDL, LDL, or both. Premature atherosclerosis.

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18
Q

Regarding the primary hyperlipoproteinemias:
What is the defect present in familial hypercholesterolemia (FH)?
How does it manifest?

A

LDL receptor, ApoB defect. Decreased receptor mediated removal of LDL from plasma
Manifestation: LDL increased, premature atherosclerosis

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19
Q

Regarding the MOA of cholesterol lowering drugs:

How do HMG-CoA reductase inhibitors (STATINS) work?

A

Inhibits rate-limiting step of cholesterol synthesis

Lowers LDL by 25-60%

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20
Q

Regarding the MOA of cholesterol lowering drugs:

How do bile acid resins work?

A

Bind to bile acids, preventing reabsorption and re-use of bile acid cholesterol
Lowers LDL by up to 20%

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21
Q

Regarding the MOA of cholesterol lowering drugs:

How does Ezetimibe (Zetia) work?

A

Prevents absorption of dietary cholesterol.

Lowers LDL by up to 20%

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22
Q

Regarding the MOA of cholesterol lowering drugs:

How does Niacin work?

A

Reduces VLDL synthesis

Lowers LDL by up to 20%

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23
Q

Regarding the MOA of cholesterol lowering drugs:

What is a mechanism shared by all of them?

A

Increase LDL receptors

Promote uptake of LDL

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24
Q

What is a downside of use of statins on health outcomes for the pt?

A

Increased chance of hemorrhagic stroke

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25
Q

Of the statins:
Lovastatin, Pravastatin, Rosuvastatin, Simvastatin, Atorvastatin
Which are inactive lactone pro drugs that are lipid soluble, metabolized by CYP3A4 and have intermediate potency/efficacy?

A

Lovastatin, Simvastatin

Memory aid: I LOVed the SIMs game, but not as much as skull CRushing games (CR for Rosuvastatin [Crestor])

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26
Q

Of the statins:
Lovastatin, Pravastatin, Rosuvastatin, Simvastatin, Atorvastatin
Which are flourine containing congeners, active as given, have a long plasma half-life, and have high potency/efficacy?

A

Atorvastatin (Lipitor), Rosuvastatin (Crestor)

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27
Q

Of the statins:
Lovastatin, Pravastatin, Rosuvastatin, Simvastatin, Atorvastatin
Which are water soluble, active, have an open lactone ring, and have low potency/efficacy?

A

Pravastatin (P is for Pitiful drug)

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28
Q

How do statins upregulate hepatic LDL receptors?

A

By promoting ER to Golgi transport and cleavage of SREBP

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29
Q

If you feel high-intensity statin treatment is indicated (> 50% reduction in LDL), what drugs would you treat with?

A

Rosuvastatin (more potent) or Atorvastatin (less potent)

30
Q

If you feel moderate-intensity statin treatment is indicated (20-50% reduction in LDL), what drugs would you treat with?

A

Any of the statins. Give the high-intensity statins at ~1/4 dose compared to HI therapy.

31
Q

If you feel low-intensity therapy (<30% reduction in LDL) is indicated, what drugs would you treat with?

A

Any except HI therapy (Atorvastatin, Rosuvastatin)

Given at ~1/4-1/2 dose compared to moderate-intensity therapy

32
Q

If you’ve got a pt < 75yo with known atherosclerotic CVD with no safety concerns, what therapy do they get?

A

High-intensity statin

33
Q

If you’ve got a pt with known atherosclerotic CVD > 75yo or < 75yo with safety concerns, what type of therapy do they get?

A

moderate-intensity statin

34
Q

If you’ve got a pt with LDL-C levels >190 mg/dL, older than 21, what therapy do they get?

A

high-intensity statin. May consider adding non-statin LDL lowering drugs to further reduce LDL

35
Q

You’ve got a pt with diabetes and no atherosclerotic CVD (ASCVD) age 40-75 with LDL 70-189 mg/dL. How do you treat them?

A

Estimate 10 yr ASCVD risk.

Mederate-intensity statin when 10-yr ASCVD is 7.5%

36
Q

If you have a pt aged 40-75 WITHOUT ASCVD or diabetes with an LDL 70-189, how do you treat them?

A

Estimate 10 yr ASCVD risk.
Persons with >7.5% 10yr risk: moderate or high intensity statin
Persons with 5%-7.4% 10yr risk: consider moderate intensity statin
Other considerations: +FH, HsCRP >2 mg/L, CCA > 300 AU, ABI < 0.9 (Ankle Brachial Index?)

37
Q

The statins are excreted primarily by what route?

A

Fecal

38
Q

Which statins are metabolized in the liver by CYP3A4?

A

Simvastatin (entirely dependent on CYP3A4)
Lovastatin
Atorvastatin

39
Q

Which statins are metabolized in the liver by CYP2C9?

A

Fluvastatin, Rosuvastatin (minimally)

40
Q

If you take nothing else from statin metabolism, what CYPs metabolize the important statins?

A

CYP3A4 and CYP2C9

41
Q

Name some things that inhibit CYP3A4 metabolism of statins.

A

Macrolide Abx: erythromycin, clarithromycin
azole antifungals taken orally
Select SSRIs (nefazodone)
Ca2+ channel blockers (verapamil, diltiazem)
Grapefruit juice (>1 quart daily)
HIV protease inhibitors (the -navirs)
immunosuppressants (cyclosporine)

42
Q

List some shit that inhibits p-glycoprotein mediated intestinal absorption of statins.

A

Dat G-fruit joose.

Cyclosporine (immunosup.)

43
Q

What are the most common ADEs of HMG-CoA reductase inhibitors?

A

Mild transient GI distress
Increased liver enzymes
sleep disturbance, reduced daytime vigilance (decreased baller status), memory loss
Teratogenic potential: Pregnancy category X!

44
Q

What are among the oldest (and safest) hypolipidemic drugs, safely used in kids and pts with liver disease?

A

Bile acid sequestrants

45
Q

Do bile acid sequestrants lower TG levels?

A

No, may increase

46
Q

What are some gastrointestinal ADEs of bile acid sequestrants?

A

bloating and constipation

47
Q

When trying to remember the names of the bile acid sequestrants, think:

A

Bile “sequestered (stored)” in gallbladder.
Gallbladder removal called cholecystectomy
Reduce bile acid re-use with colest- or cholest- drugs.
You’re also reducing cholesterol uptake…so…

48
Q

What is a drug interaction to remember with bile acid sequestrants (BAS)?

A

BAS prevent absorption of other drugs: digoxin, beta-blockers, thyroxine, coumadin. So take other meds 1 hr before or 3-4 hrs after BAS.

49
Q

What are some contraindications of bile acid sequestrant (BAS) use?

A

hypertriglyceridemia
Complex drug regimens and critical medications
history of constipation (elderly pts)

50
Q

Ezetimibe is similar to bile acid sequestrants in that it reduces cholesterol uptake in the intestines, but differs in this mechanism:

A

It prevents intestinal uptake of cholesterol itself (in small intestine)

51
Q

What effect do cholesterol uptake inhibitors or synthesis inhibitors have on LDL receptor levels and thus, plasma LDL levels?

A

They up-regulate LDL receptor levels, increasing clearance of LDL from plasma.

52
Q

What are the drugs that primarily lower TG levels and raise HDL-cholesterol?

A

Fibric Acid Derivatives (Fibrates)
Nicotinic Acid (Niacin)
Omega-3 Polyunsaturated fatty acids (fish oil)

53
Q

What are the fibric acid derivatives and how do they work?

A

Gemfibrozil (generic)
Fenofibrate (Tricor)
MOA: ligand for the ligand activated PPARalpha nuclear receptor. Decreasing synthesis of ApoC-III, increasing synthesis of ApoA-I and ApoA-II by liver. Decreasing synthesis and secretion of TGs from liver.

54
Q

What are the lipoprotein effects of Fibrates (i.e. what is increased, reduced)?

A 
Reduce VLDL
Increase HDL
TGs reduced up to 50%
HDL-C increased up to 15%
LDL-C unchanged or decreased modestly (may increase)
55
Q

What are the ADEs of fibrates?

A

gastroesophageal reflux, diarrhea, increased hepatic enzymes.
Fenofibrate: paradoxical HDL lowering
Gallstones
Pregnancy category C (use only if benefit outweighs risk)

56
Q

What metabolizes Gemfibrozil?

A

liver, UTG1A1.

Gemfibrozil reduces statin metabolism because UTG1A1 is used in statin biotransformation

57
Q

Which fibrate can be safely administered in pts with renal insufficiency?

A

Gemfibrozil.

Fenofibrate not recommended because it accumulates when GFR < 30 ml/min (advanced renal disease)

58
Q

Describe the MOA of niacin in reducing TG levels.

A

Inhibits mobilization of FFA from adipocytes.
Reduces hepatic TG synthesis
Reduces hepatic ApoB synthesis and secretion (VLDL)
Enhances ATP cassette mediated transfer of cholesterol from macrophage to HDL
Promotes conversion of VLDL to LDL via enhanced Lipoprotein Lipase

59
Q

Which vitamin is niacin?

A

Vit B3 aka nicotinic acid

60
Q

What effects does niacin have on the lipoproteins, as far as raising and lowering their levels?

A 
Increases HDL-C by 15-35%
Reduces LDL-C by 5-25%
Reduces TG by 20-50%
Shifts LDL density to larger particles
Reduces Lp(a) by 30% (unique feature)
61
Q

Niacin has a greater impact on TG or Cholesterol levels?

A

TG

62
Q

Describe the ADEs of Niacin.

A

Cutaneous flushing- use extended release to avoid
Elevated Hepatic enzymes
GI discomfort
Hyperuremia/gout
Eye problems (conjunctivitis, macular edema, retinal detachment)
Dry skin
Insulin resistance
Pregnancy category C: use if benefit exceeds risk

63
Q

Does addition of Niacin or Fibrate to Statin therapy further reduce risk of CVD?

A

No

64
Q

What effect does Omaga-3 fatty acid have on CVD risk?

A

Reduces TGs (by up to 35%) and CVD risk.
Antiplatelet, hypotensive, hypolipidemic effects
Studies show: eat fish, don’t bother with capsules. Studies using concentrated fish oil (EPA and/or DHA currently underway)
Studies show eating a serving of cold water fish 1 or more servings/week reduces CVD risk.

65
Q

Describe the relationship between HDL-C and coronary heart disease (CHD) risk.

A

For every .5mg/dL of HDL-C, CHD risk decreased by 50%.

66
Q

What is CETP and what does it do?

A

Plasma protein that catalyzes the transfer of CE from HDL to ApoB-containing lipoproteins (VLDL & LDL) in exchange for TG.
CETP is BAD
We want CETP levels to be LOW so that HDL levels will be high.
CETP inhibitors have not shown to have a CVD benefit, despite raising HDL levels

67
Q

What are Anacetrapib and evacetrapib?

A

CETP inhibitors.
Have been shown to dramatically increase HDL-C and lower LDL-C by 30-40%.
Still no proven effect of CVD.

68
Q

You draw blood from a younger pt who you suspect has acute pancreatitis. She also has markedly elevated TGs and cholesterol, and eruptive xanthomas. You let the drawn blood sit overnight in the refrigerator and the next morning the plasma shows a white, creamy precipitate on the top, what is going on?

A

Primary chylomicronemia

All the white cream are chylomicrons

69
Q

The most potent cholesterol lowering drugs are statins, bile acid sequestrants, direct Cho absorption inhibitors, or naicin?

A

Statins all the way baby

25-60% reduction of LDL compared to up to 20% for the rest

70
Q

Your pt has had an MI recently and has an LDL level of 170mg/dL. Of the various cho lowering drug classes, what will you Rx?

A

Statin. Atorvastatin or Rosuvastatin

71
Q

Describe the bioavailability of statins in one word or less.

A

Shit<25%ty

Cardiovascular (10 decks)

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