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Cardio Module > 4. Olah - Dyslipidemias > Flashcards

4. Olah - Dyslipidemias Flashcards

1
Q

TGs, from where and functions

A

Trimester of glycerol and fatty acid
Obtained from biosynthesis and diet
Functions: energy source and storage

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2
Q

Lipoproteins function

A

Activate enzymes, receptors and transporters

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3
Q

What is the rate limiting step in cholesterol synthesis?

A

HMC-CoA Reductase

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4
Q

Cholesterol Metabolism and Transport

A

VLDL from hepatic synthesis –> apoproteins allow it to enter capillaries, muscles and fat –> Lipoprotein lipase generate IDL –> Hepatic lipase removes more TGs from IDL creating LDL –> LDL transported to liver and peripheral cells

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5
Q

What is the benefit of HDLs

A

Anti-atherogenic effects from the role in Reverse Cholesterol Transport

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6
Q

What are HDL’s anti-atherogenic effects?

Hint, there’s 5

A
  1. Antioxidant
  2. Endothelial cell protectant
  3. Anti-inflammatory
  4. Anti-platelet and anticoagulant
  5. Profibrinolytic
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7
Q

What are the 5 main drugs in treatment of dyslipidemia?

A
  1. HMG-CoA Reductase Inhibitor
  2. Ezitimibe
  3. Bile Acid Sequestrants
  4. Niacin (Nicotinic Acid)
  5. PPAR-alpha Activators (Fibrates)
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8
Q

HMG-CoA Reductase Inhibitors are also known as…

A

Statins

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9
Q

MOA of Statins

A

Reversible competitive inhibitors of HMG-CoA Reductase - primarily in hepatocytes

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10
Q

What do statins do to lipid profile?

Hint, how are LDL, TGs, and HDL affected

A

Decrease in LDLs
Decrease in TGs - only if pt has high baseline TG
Increases in HDL - only if pt has low baseline HDL

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11
Q

What are statins other MOA?

Hint, has to do w/ LDL

A

Since there is a reduction in overall cholesterol, the SREBP pathway senses low LDL levels and synthesizes more LDL receptors. An increase in LDL receptors will lead to an increase in LDL taken into the cell, contributing to a decrease in circulating LDL levels

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12
Q

What is stain “pleiotropy”?

A

Decrease in cholesterol that is necessary for the anchoring of small G-proteins

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13
Q

What are the benefits of statin pleiotropy?

Hint, there’s 5

A
  1. Effects on endothelial cells - increase eNOS, antioxidant effect
  2. Anti-platelet effect
  3. Effects on vascular smooth muscle cells
  4. Inhibit macrophage accumulation
  5. Increase plaque stability
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14
Q

What is the main side effect of statin therapy?

A

Myopathy, aka muscle pains

This can lead to myosotis (muscle spasms) or to rhabdomyolysis (breakdown of skeletal muscle)

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15
Q

What can increase the incidence of myopathy associated w/ stains?
(Hint, it’s a certain drug example)

A

Gemfibrozil competing for the transport into cells

This causes an increase of circulating statins, which can lead to increase toxicity

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16
Q

How does gemfibrozil affect hepatic metabolism of statins?

Hint, there’s 2 ways

A
  1. Competes for CYP2C9 metabolism –> increasing circulating statins
  2. Inhibits glucuronidation of stains - no breakdown of statins, stay out in circulation
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17
Q

What are the 3 proposed mechanism for statin-induced myopathy?

A
  1. Effect on membrane integrity
  2. Effect on small g-proteins, such as Rho and Rac
  3. Decreased ubiquinone, though to be involved in energy production
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18
Q

What are the two other adverse effects/contraindications of statins besides for myopathy?

A
  1. Hepatotoxicity

2. Pregnancy - avoid statins when pregnant

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19
Q

What is Ezitimibe’s MOA?

A

Inhibits intestinal uptake of cholesterol by blocking the intestinal receptor for dietary cholesterol - NPC1L1 receptor on the luminal side

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20
Q

What is Ezitimibe’s effect on lipoproteins?

Hint, LDL, TGs, and HDL

A

Decreased LDLs
Slight decrease in TGs
Very little increase in HDL (~1-2%)

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21
Q

What can Ezetimbe be combined w/?

A

Ezetimbe and statin (simvastatin)

  • knocks out each other’s compensatory mechanism
  • decreases cholesterol uptake and synthesis
22
Q

Uses for Ezetimbe

Hint, there’s 3

A
  1. Monotherapy to lower LDL
  2. Combotherapy w/ a statin
  3. Sitosterolemia - blocks the inappropriate absorption of plant sterol
23
Q

Clinical toxicity of Ezetimbe

A

W/ along - similar to placebo

W/ statin - similar to statins

24
Q

Ezetimbe drug interaction

A

Avoid concurrent administration w/ bile acid sequestransts

- inhibits the absorption of Ezetimbe

25
Q

Bile Acid Sequestrants

Examples and MOA

A

Examples: cholestyramine, colestipol, colesevelam
MOA: interfering w/ enterohepatic recirculation of bile acids
- binds to bile acids and causes them to not be reabsorbed, and are easily excreted out through feces

26
Q

Bile Acid Sequestrants effect on the lipid profile

Hint, LDL, TG and HDL levels

A

Decrease in LDLs
Very small INCREASE in TGs when baseline is high
Small increase in HDL (~5%)

27
Q

Bile Acid Sequestrants Toxicity

A

No systemic effects

Can cause GI problems

28
Q

Bile Acid Sequestrants Drug-Drug Interactions and how to avoid interactions

A

Interfere w/ the absorption of many drugs
Ex. Digoxin, propranolol, etc.
Should administer 1 hour before or 4-6 hours after bile acid sequestrant

29
Q

Niacin and its MOA (multiple)

A

Niacin - a vitamin B complex
MOA:
- to decrease TG and LDL: in adipose to decrease TG lipolysis and enhance activity of hepatic LPL
- to increase HDL: increase plasma levels of ApoA-1 (building block of HLD)

30
Q

How does Niacin affect the lipid profile?

Hint, LDL, TGs and HDL affected?

A

WIDESPREAD BENEFIT!
Significant decrease in LDL
Significant decrease in TGs
Significant increase in HDL - the best agent for this

31
Q

Niacin and toxicity

Hint, there’s 5

A
  1. Flushing - typically initial therapy or immediate release
  2. Hepatotoxicity - usually from sustained release
  3. Hyperglycemia - caution w/ diabetics
  4. Increased uric acid - caution w/ gout
  5. Dyspepsia - upset stomach
32
Q

PPAR-alpha activators (Fibrates, Fibric acid derivatives)

Examples and how it acts

A

Examples: Clofibrate, Gemfibrozil, Fenofibrate
How it acts: nuclear receptor/transcription factor, will promote the oxidation of free fatty acids –> leading to decreased FFAs for production of TGs –> decreased TGs

33
Q

PPAR-alpha activators MOA

Hint, there’s 2

A
  1. Promote oxidation of FFA –> upregulate FFA into cell –> primes and modifies FFA –> upregulates enzymes to prove oxidation
  2. Increase expression and/or activity of lipoprotein lipase –> increase the metabolism of TGs
34
Q

PPAR-alpha Activators effect on the lipid profile

Hint, LDL, TGs and HDL

A

Major: decrease ~50% of TGs if baseline is over 400 mg/dL
Decrease VLDL
Might see increase LDL
Might increase HDL

35
Q

PPAR-alpha activators and their non-lipid anti-atherogenic effects
(Hint, there’s 4)

A
  1. Macrophage increasing cholesterol efflux for HLD particles
  2. Anti-inflammatory effects
  3. Protective endothelial effects
  4. Vascular smooth muscle - inhibit proliferation and migration
36
Q

PPAR-alpha activators toxicity

A

GI upset

Not used in pregnancy

37
Q

PPAR-alpha activators and drug-drug interactions

A
  1. Statins! - increased incidence of myopathy

2. Potentiates effects of warfarin

38
Q

What are the not so common dyslipidemic agents?

Hint, there’s 4

A
  1. Omega-3 Fatty Acids (aka fish oils)
  2. Lomitapide
  3. Mipomersen
  4. PCSK-9 inhibitors
39
Q

What are the two main agents in Omega-3 fatty acids?

A
  1. Omega-3 fatty acid ethyl esters (EPA and DHA)

2. Icosapent Ethyl (EPA only)

40
Q

Uses of omega-3 fatty acids

A

Reduction of TGs

Variable effects on LDL and HDL

41
Q

Proposed MOA of omega-3 fatty acids

A

Reduced hepatic synthesis of TGs, increase in oxidation, and increase lipoprotein lipases activity

May also be anti-inflammatory

42
Q

Toxicity of omega-3 fatty acids

A

Burping and fishy after tastes

Small incidence of bone pain, and joint pain

43
Q

Lomitapide and its use

A

For reduction of LDL in combo w/ diet and stains in pts w/ familial hypercholesterolemia

44
Q

MOA of Lomitapide

A

Inhibits microsomal transfer protein - inhibits the synthesis of chylomicrons and VLDL

45
Q

Toxicity of Lomitapide

A

Hepatotoxicity

46
Q

Mipomersen and its use

A

For combo therapy w/ statins and diet to reduce LDL in pts w/ homozygous familial hypercholesterolemia

47
Q

MOA of Mipomersen

A

Antisense oligonucleotide against ApoB100 - decreases production of ApoB100 - decreased LDL cholesterol

48
Q

Toxicity of Mipomersen

Hint, there’s 3

A
  1. Pain at injection site
  2. Flu-like symptoms
  3. Liver toxicity
49
Q

PCSK-9 Inhibitor and MOA

Alirocumab, Evolocumab

A

Inhibits the normal breakdown process of LDL receptors. Leads to more LDL receptors on the cell membrane, more LDL can go into cell, leading to decreased LDL out in circulation

50
Q

PCSK-9 Inhibitors on the lipid profile

Hint, LDL, TGs, and HLD

A

W/ or w/o statin therapy - significant decrease in LDL ~60-70%
Decrease in TGs

51
Q

Cholesterol, where is it from and what’s its function

A

Synthesized in the liver and though died

Functions: membrane constituent, steroid precursor, and bile acid formation

Cardio Module (12 decks)

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