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Cardio Week 4 > Lecture 35: Drugs Affecting Lipoprotein Metabolism > Flashcards

Lecture 35: Drugs Affecting Lipoprotein Metabolism Flashcards

1
Q

What is the paradigm for atherosclerosis generation?

A

Oxidized LDL is taken up by macrophage to form foamy macrophages

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2
Q

Who should be screened for lipids?

A

Everyone over 20 years old

Screened for triglycerides, total cholesterol, HDL, LDL

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3
Q

What is ATP when it comes to cholesterol treatment?

A

Adult Treatment Panel

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4
Q

What is the primary target of hypercholesteremia?

A

Reduction of LDL to appropriate level

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5
Q

What are the secondary goals in treating hypercholesteremia?

A
  1. Decreasing triglycerides and non-HDL cholesterol are secondary goals
  2. Increasing HDL cholesterol is also a secondary goal
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6
Q

What are LDL cholesterol goals?

A

Less than 100 or less than 70 if they have CHD
<160 if no risk factors
Highest risk below 70

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7
Q

What is a normal fasting normal TG?

A

<150
Elevated TG are independent risk factor for CHD
Because they are transported by the lipoproteins

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8
Q

What are non-HDL-C?

A

VLDL + IDL + LDL
Signficance is now we are trying to target other non-HDL
Aside from LDL
Also a risk factor for CHD

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9
Q

What is the non-HDL-C target?

A

30 mg/dL higher than LDL-C target

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10
Q

What is considered low HDL?

A

<40

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11
Q

What is the non-pharmacologic therapy for lipid disorders?

A
  1. Diet
  2. exercise and weight loss
  3. avoidance of alcohol intake
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12
Q

What are the purposes of the drugs for treatment of lipid disorders?

A
  1. reduce LDL-C
    i. HMG-CoA Reductase Inhibitors
    ii. Cholesterol Absorption Inhibitors
    iii. Bile Acid Sequestrants
  2. treat TG-HDL axis
    i. Fibrates (Fibric Acid Derivatives)
    ii. Omega 3 Fish Oil
    iii. Niacin (Nicotinic Acid)
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13
Q

What are drugs that reduce LDL-C?

A
  1. HMG CoA reductase inhibitors (statins)
  2. cholesterol absorption inhibitors (CAI; ezetimibe)
  3. Bile acid sequestrants (BAS)
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14
Q

What are examples of different types of statins?

A

Always has a “statin” in the generic name

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15
Q

What is the MoA of statins?

A

Inhibits cholesterol synthesis
Targets rate limiting step of cholesterol synthesis
MoA = HMG-CoA Reductase Inhibitor
Statin mimics HMG-CoA so competitively binds
To HMG-CoA reductase
-reversible but has much greater affinity
Than normal HMG-CoA

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16
Q

How is the LDL receptor regulated?

A

Regulated by the amount of cholesterol in the liver
So if you have less cholesterol in the liver, you upregulate the production and migration of the LDL receptor to the liver surface
Thus, statins will decrease cholesterol synthesis which then upregulates LDLReceptors

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17
Q

Why are there very few adverse effects of statins?

A

Because body upregulates HMG-CoA reductase/LDL receptors to compensate for less cholesterol synthesis
Therefore, total cholesterol level remains about the same even though LDL is reduced in blood

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18
Q

What is the first line therapy for LDL reduction?

A

Statins

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19
Q

What are the adverse effects of statins?

A
  1. Elevated hepatic transaminases (not a big deal)
  2. muscle-related adverse effects
    i. myalgia
    ii. myopathy
    iii. rhabdomyolysis
    Dose-dependent
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20
Q

Do statins still work if you eat McDonalds every day?

A

Yep

21
Q

What is myalgia?

A

Muscle ache or weakness without creatine kinase elevation

22
Q

What is myopathy?

A

Muscle symptoms with increased CK levels

23
Q

What is rhabdomyolysis?

A

Muscle symptoms with makred CK elevation and with creatinine elevation
Brown urine and myoglobin

24
Q

What are risk factors for statin-induced myopathy?

A
  1. age, gender (female)
  2. frailty, low body weight
  3. renal insufficiency
  4. hypothyroidism
25
Q

Why do we need drug classes aside from statins?

A

Because of the side effects of statin for certain populations

26
Q

How is cholesterol absorbed?

A

NPC1L1 transporters take up cholesterol into duodenal/jejunal enterocytes
IBAT transporters also take up cholesterol into ileal enterocytes

27
Q

How is cholesterol transported from enterocytes back out to lumen?

A

By ABC transporters

28
Q

What are cholesterol Absorption Inhibitors?

A

Prevents absorption of cholesterol from small intestine (which is 25% diet and 75% from liver)
Increases LDL receptors ultimately!

29
Q

What is the MoA of Ezetimibe?

A

Inhibits NPC1L1

Thus inhibits cholesterol uptake in enterocytes

30
Q

What is the efficacy of Ezetimibe?

A

Reduces LDL by 20% as monotherapy
Minimal effects on TG
Not yet shown to reduce CV events on own
Usually added to statin therapy or used for those who cant tolerate statins

31
Q

What are the adverse effects of ezetimibe?

A

Elevated transaminases

32
Q

What are the key characteristics of bile acid sequestrants?

A

MoA: binds bile acids in the lumen and promotes its excretion
Prevents bile acids from being reabsorbed because the resulting complex is so big
Example:
i. cholestyramine
ii. Colestipol
iii. Colesevelam
Ultimately leads to upregulation of LDL receptors

33
Q

What are the indications for bile acid sequestrants?

A
  1. statin intolerant patients or to add to statin therapy
    Reduction of 15% by itself
    Can raise TG levels and has minimal effects on HDL-C
34
Q

What are the adverse effects of bile acid sequestrants?

A
  1. drugs are not absorbed systemically and lack systemic toxicity
  2. result in constipation, bloating, flatulence, heartburn and nausea
  3. can interfere with absorption of other drugs
  4. can raise TG levels
35
Q

What are the similarities among statins, CAI, and bile acid sequestrants?

A

All 3 ultimately lead to upregulation of LDLR

36
Q

What can lower LDL aside from drugs and exercise?

A

LDL apheresis (takes blood from patient and purges LDL cholesterol, like dialysis machine)

37
Q

What is the significance of PCSK9?

A

PCSK9 downregulates LDL-receptors

Thus, we can target PCSK9 and inhibit the motherfucker, thereby upregulating LDLreceptors

38
Q

How are triglycerides and HDL related?

A

Things that raise TG will lower HDL

Inversely related

39
Q

What are the three drugs that target the TG-HDL axis?

A
  1. Fibric Acid Derivatives (Fibrates)
  2. Omega 3 Fatty acids (fish oils)
  3. Nicotinic Acid (niacin)
40
Q

What are examples of fibrates?

A

Fenofibrate, Clofibrate, Gemifibrozil

41
Q

What is the MOA of fibrates (fibric acid derivatives)?

A

Activates the nuclear PPARalpha receptor in liver and peripheral tissues
Decreases ApoC-III = less VLDL
Increases Acyl-CoA synthase = decrease FFA
Increase ApoA1, ApoA2, ABCA1 = increased HDL in blood

42
Q

What is the efficacy of fibrates?

A
  1. decrease TG levels by up to 50%
  2. Increase HDL by 20%
    But CV outcome trials have yielded mixed results
    Only use with hypertriglyceridemia
43
Q

What are the adverse effects of fibrates?

A
  1. typically well tolerated
  2. can cause myalgia/myopathy
  3. potentiate action of oral anticoagulants
44
Q

What is the MoA of Omega 3 fatty acids?

A

Contains EPA and DHA
Reduces TG levels by 50%
Increases hDL by 10%

45
Q

What is the MoA of niacin (nicotinic acid)?

A

Binds to niacin receptor on adipocyte
Decreases cAMP which downregulates
The conversion of TG to FFA
Reduces FFA release and flux to liver

46
Q

What is the niacin efficacy?

A

Increase HDL = 20%
Decrease TG levels by 20%
Decrease LDL by 15%
Decrease Lp(a) by 15%

47
Q

What is the primary adverse effect in niacin?

A

Flushing = 88% patients

48
Q

What are cholesteryl ester transfer protein (CETP) inhibitors?

A

CETP converts HDL to LDL
Inhibitors therefore will increase HDL levels because there is no change of HDL to LDL
Time will tell if this works

Cardio Week 4 (12 decks)

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