Hyperlipidemia- Kearns

These flashcards are easier than what Kearns is gonna ask.

Hyperlipidemia = high ________________

cholesterol

Lipids are insoluble in plasma and are transported by _________________.

lipoproteins

What are the 4 major types of lipoproteins?

1. Chylomicrons

2. VLDL

3. LDL

4. HDL

What is the name of the genetic disorder where a mutation in lipoproteins causes lipids to be incorrectly metabolized?

hyperproteinlipidemia

If a pt had hyperproteinlipidemia and had problems with their VLDL lipoproteins, what would you expect to see?

• lipids to stay in the cells

• increase in bile

If a pt had hyperproteinlipidemia and had problems with their LDL lipoproteins, where would you expect lipids to accumulate?

in the blood

If I had a lipid panel, would it be a good idea to use my LDL-C value to diagnose?

no

Hyperproteinlipidemia is a disorder that may lead to the buildup of which of the following in the systemic circulation? SATA

a. LDL

b. HDL

c. triglycerides

d. cholesterol

ALL

What are some of the reasons we need cholesterol?

• cell membrane component

• hormone production

• produce bile salts

• synthesize Vit D

• helps nervous system

• mood/stress stabilizer

What are the 2 strategies for CV prevention dealing with cholesterol?

1. lower LDLs

2. increase HDLs

LDLs are mostly _________ and HDLs are mostly ___________.

LDLs are mostly lipids and HDLs are mostly protein.

VLDLs are the primary carriers of ________________.

triglycerides

What makes up the core of a lipoprotein?

• cholesterol esters

• triglycerides

What makes up the outer layer of the lipoprotein?

• apolipoprotein

• free cholesterol

• phospholipids

What are examples of pro-atherogenic molecules?

• chylomicron remnants

• VLDL

• LDL

What are examples of anti-atherogenic?

• HDL

What are the functions of apolipoproteins?

• structure

• ligands

• activators or inhibitors of enzymes in the metabolism of lipoproteins

A lipid blood test detected by measuring lipids in serum after a _____-hour fast.

10

Risk of Heart Disease increases with

• _______-atherogenic lipoproteins

• HDL <____ mg/dL

• LDL >______mg/dL

• triglycerides >_______mg/dL

• pro-atherogenic lipoproteins

• HDL <40 mg/dL

• LDL >160 mg/dL

• triglycerides >200 mg/dL

What is the optimal and high, Total Cholesterol (mg/dL)?

• optimal <200

• high >239

What is the optimal and high, LDL (mg/dL)?

• optimal <130

• high >159

What is the optimal and high, HDL (mg/dL)?

• optimal >60

• high <40

What is the optimal and high, triglycerides (mg/dL)?

• optimal <150

• high >199

What is the optimal and high, Non-HDL-C (mg/dL)?

• optimal <130

• high >159

(Think: same as LDL)

PRACTICE:

Would an LDL value of 129 mg/dL be considered high, intermediate, or optimal?

optimal

PRACTICE:

Would an HDL value of 50 mg/dL, would that be considered high, intermediate, or optimal?

intermediate (between 40-60)

PRACTICE:

If I had a triglyceride level of 201 mg/dL, would that be considered high, intermediate, or optimal?

high

Which pathway deals with dietary cholesterol? (endogenous or exogenous)

exogenous

Briefly explain how the exogenous pathway works:

dietary lipids—> chylomicrons—> chylomicron full of TG in circulation—> TG are metabolized by muscles and fat by LPL—> chylomicron remnants are transported to the liver

Briefly explain how the endogenous pathway works:

liver—> VLDL formation—> VLDL metabolized to release fatty acids—>IDL—>LDL—>LDL taken up by LDLRs

What lipoprotein is used in reverse cholesterol transport? (LDL,VLDL,HDL, Chylomicron)

HDL

Enterohepatic circulation of bile acids includes what 3 steps?

1. bile acids secreted by __________ to __________________.

2. bile acids are stored in the __________________.

3. after a meal, bile acids are secreted into the _________________ then either absorbed by the _______________ or transported back to the ____________.

1. bile acids secreted by liver to gallbladder

2. bile acids are stored in the gallbladder

3. after a meal, bile acids are secreted into the intestine then either absorbed by the enterocyte or transported back to the liver.

What would happen if the gallbladder was removed?

we wouldn’t be able to store bile

After a meal what is secreted by the duodenal mucosa?

Cholecystokinin (CCK)

Cholecystokinin stimulates what?

release of bile from the gallbladder

After bile is released, micelles are formed, what is released from the pancreas to hydrolyze the triglycerides in that micelle?

Lipase!!

The threshold cholesterol conc for micelle formation is _________mmol/L.

1.5

After a large meal the bile acid conc in the small intestine is between ____-_____mmol/L

5-10

Enterohepatic Recycling allows drugs to do what?

1. provides a secondary absorption phase

2. prolongs t_1/2

3. produces multiple peaks in plasma conc time

What transporter allows micelles and cholesterol to enter the enterocyte from the intestinal lumen?

NPC1L1

What protein is attached to the chylomicron and is a sign of chylomicron metabolism?

Apo B-48

If we had a mutation in the NPC1L1 transporter, does that mean we have a 0% risk of hyperlipidemia?

NO- we still have the endogenous pathway that could be causing hyperlipidemia

What enzyme do Statins inhibit?

HMG-CoA Reductase

If I had diabetes, how would that affect my lipid metabolism?

• increase in Acetyl CoA causes increase in HMG-CoA

• result: extra cholesterol production

What are the names of the 2 PCSK9 inhibitors that are humanized Antibodies?

1. Alirocumab

2. Evolocumab

What is the name of the PCSK9 Inhibitor that is an siRNA?

Inclisiran

The BIG PICTURE of PCSK9 inhibitors is that it allows for ____________ to be recycled.

allows for RECEPTORS to be recycled

For intra and extra cellular PCSK9, out of EVERYTHING, the only mechanisms that are upregulated are what?

• Apo B-48, NPC1L1, Apo-A

• EVERYTHING ELSE IS DOWNREGULATED

Familial Hypercholesterolemia is what type of disorder?

a. autosomal recessive

b. sex-linked recessive

c. autosomal dominant

d. sex-linked dominant

c- AUTOSOMAL DOMINANT

For familial hypercholesterolemia, heterozygous (Cc) individuals have cholesterol levels between _______ to _______ mg/dL.

260 to 500 mg/dL

For familial hypercholesterolemia, homozygous (CC) individuals have cholesterol levels >_______mg/dL.

>1000 mg/dL

Does familial hypercholesterolemia, deal with the endogenous or exogenous pathway?

endogenous

If you have familial hypercholesterolemia, there is either a decreased or inability to produce __________.

a. HDLs

b. LDLRs

c. VLDLs

d. Lipase

b

List the brand name for each of the following statins:

• Rosuvastatin

• Atorvastatin

• Simvastatin

• Lovastatin

• Pravastatin

• Fluvastatin

• Rosuvastatin- Crestor

• Atorvastatin- Lipitor

• Simvastatin- Zocor, Flolipid

• Lovastatin- Mevacor, Altoprev

• Pravastatin- Pravachol

• Fluvastatin- Lescol

All statins are indicated in cases of…

• primary hypercholesterolemia

• mixed dyslipidemia

What is the pleiotropic (secondary) effect of Statins?

• decrease vascular inflammation as atherosclerotic lesions stabilize

Do statins possess low or high systemic bioavailability?

low

A good counseling points of statins is to take them with __________.

water

Which of the statins are prodrugs?

• Lovastatin

• Simvastatin

Which of the statins are hydrophilic? What groups allow them to be hydrophilic?

• Rosuvastatin- sulfonamide

• Pravastatin- carboxylic acid/carboxylate

Which statins are non-lactone/fluorinated statins?

• atorvastatin

• fluvastatin

• rosuvastatin

Lovastatin is converted to it’s active metabolite through what reaction? Additionally, what group is modified in that reaction?

• converted through hydrolysis

• lactone group is modified

Which of the statins are metabolized by CYP2C9?

• fluvastatin

• rosuvastatin

Which of the statins are metabolized by CYP3A4?

• Atorvastatin

• Lovastatin

• Simvastatin

Which of the statins are not metabolized by any of the CYPs?

pravastatin

Each statin and their drug interactions:

• just a helpful table I made for reference:

TIPS:

• Look at the CYP of each drug- all CYP3A4’s have similar interactions

• Cyclosporine interacts w/ everything but Fluvastatin

• Fluvastatin doesn’t react with any of the drugs Kearns wants us to know, while Lovastatin reacts with everything

• -Sarah Kiser, said she remembered they asked about antidepressants on her exam so make note of that-

Drug	Drug Interactions
Atorvastatin (CYP3A4)	Azole Antifungals Non-DHPs (rare) Cyclosporine Antidepressants
Fluvastatin (CYP2C9)	Nothing
Lovastatin (CYP3A4)	Azole Antifungals Non-DHPs Cyclosporine Antidepressants Macrolide Antibiotics Warfarin
Pravastatin (no CYP)	Cyclosporine
Rosuvastatin (CYP2C9)	Cyclosporine Warfarin
Simvastatin (CYP3A4)	Azole Antifungals Non-DHPs Cyclosporine Antidepressants Macrolide Antibiotics

What are the Drug Interactions for Atorvastatin?

Specifically, does it interact with:

• Azole antifungals

• Non-DHPs

• Cyclosporine

• Macrolide Antibiotics (-mycin)

• Warfarin

• Antidepressants

• azole antifungals

• non-DHPs

• Cyclosporine

• Antidepressants

What are the Drug Interactions for Fluvastatin?

Specifically, does it interact with:

• azole antifungals

• Non-DHPs

• Cyclosporine

• Macrolide Antibiotics (-mycin)

• Warfarin

• Antidepressants

NONE OF THESE

What are the Drug Interactions for Lovastatin?

Specifically, does it interact with:

• azole antifungals

• Non-DHPs

• Cyclosporine

• Macrolide Antibiotics (-mycin)

• Warfarin

• Antidepressants

ALL OF THESE

What are the Drug Interactions for Pravastatin?

Specifically, does it interact with:

• azole antifungals

• Non-DHPs

• Cyclosporine

• Macrolide Antibiotics (-mycin)

• Warfarin

• Antidepressants

Cyclosporine

What are the Drug Interactions for Rosuvastatin?

Specifically, does it interact with:

• azole antifungals

• Non-DHPs

• Cyclosporine

• Macrolide Antibiotics (-mycin)

• Warfarin

• Antidepressants

Cyclosporine

Warfarin

What are the Drug Interactions for Simvastatin?

Specifically, does it interact with:

• azole antifungals

• Non-DHPs

• Cyclosporine

• Macrolide Antibiotics (-mycin)

• Warfarin

• Antidepressants

• azole antifungals

• non-DHPs

• Cyclosporine

• Antidepressants

• Macrolide Antibiotics

PRACTICE:

Which of the following statins would interact with Warfarin? SATA

a. Crestor

b. Lipitor

c. Mevacor

d. Pravachol

a, c

What is the most common add-on tx with statins and why?

• Ezetimibe (Zetia)

  • bc PCSK9 inhibitors are expensive

How does Niacin effect the…

• endogenous pathway

• exogenous pathway

• and it’s overall goal

• endogenous

  • decreases TG synthesis—> decreases VLDL formation—> decreases FFA and LDL—> increases HDL

• exogenous

  • increases chylomicron removal from plasma

• overall goal:

  • increase HDL

  • decrease LDL, TG

Fibrates are ligands for NFT PPAR-a and up-regulate what? Additionally, what is the goal of fibrates?

up-regulate LPL, apo A-I, and apo A-II

goal: decrease VLDL, Increase HDL

Which has a longer half-life… Gemfibrozil or Fenofibrate?

Fenofibrate

What are the warnings with fibrates?

• avoid in hepatic/renal dysfunction

• should not give with Ezetimibe or Statins

Fibrates could be combined with…

niacin or PSCK9 Inhibitor

What is the active metabolite of Fenofibrate?

Fenofibric acid (Trilipix)

What are the generic names of Bile acid sequestrants and when are they used?

Names: “The C’s” Colesevelam, Colestipol, Cholestyramine

Used: In isolated LDL increases

MOA of Bile acid sequestrants:

• bind to bile acids in the intestinal lumen and prevent their reabsorption

  • effects exogenous

Bile acid sequestrants… pos or neg feedback?

negative feedback

Toxicity warning of bile acid sequestrants and what to do because of that:

• absorption of certain drugs may be impaired

  • give those meds 1 hr before or 2 hrs after taking

Ezetimibe is a ________________ absorption inhibitor. The goal is to decrease _______.

cholesterol, LDL

What transporter does Ezetimibe block?

NPC1L1

PRACTICE:

If I wanted a statin that stayed in my plasma longer, which of the following would I chose?

a. Lipitor

b. Zocor

c. Mevacor

d. Lescol

d

Toxicity warning of Ezetimibe:

prior lipid lowering therapy in combo of sterol absorption inhibition has been associated w/ coronary events

When are these 2 meds used in combo?

Fibrates + Bile acid sequestrants

• familial hyperlipidemia

  • can’t use statins/niacin

When are these 2 meds used in combo?

Statin + Bile acid sequesterants

• familial hyperlipidemia

  • bc of bile acid seq. make sure you give 1 hr before or 2 hr after

When are these 2 meds used in combo?

Niacin + Bile acid sequestrants

• HETEROZYGOUS familial hypercholesterolemia

• hyperproteinuria

When are these 2 meds used in combo?

Niacin + Statin

• hypercholesterolemia

When are these 2 meds used in combo?

Statin + Ezetimibe

• HOMOZYGOUS familial hypercholesterolemia

When are these 2 meds used in combo?

Statin + Ezetimibe + Niacin + Bile acid sequesterants

• severe disorders involving high LDL