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Flashcards in HLD drugs Deck (77):
1

High triglycerides can eventually result in what condition?

What is the recognized threshold (serum mg/dL)?

Pancreatitis

> 500 mg/dL

2

List the presently accepted values for desirable, borderline and high serum LDL-cholesterol.

  • Desireable: < 100 mg/dL
  • Borderline: 100-159 mg/dL
  • High: >190 mg/dL

3

List the presently accepted values for desirable serum HDL-cholesterol. (men vs. women).

  • Men: > 40 mg/dL
  • Women: > 50 mg/dL

4

List the presently accepted values for desirable, borderline, and high triglyceride levels. (Also, what is considered very high?)

  • Desirable: < 150 mg/dL
  • Borderline: 150-199 mg/dL
  • High: > 200 mg/dL (> 500 very high)

5

NCEP lipoprotein treatment goals: VERY HIGH RISK:

  • CV risk factors?
  • LDL goal?

 

  • Current CHD + other factors
  • < 70 mg/dL

6

NCEP lipoprotein treatment goals: HIGH RISK:

  • CV risk factors?
  • LDL goal?

  • Previous CHD, diabetes, > 2 risk factors
  • < 100 mg/dL (optional < 70)

7

NCEP lipoprotein treatment goals: MODERATELY HIGH RISK:

  • CV risk factors?
  • LDL goal?

  • > 2 risk factors. 10-20% ten-year risk
  • < 130 mg/dL (optional < 100 mg/dL)

8

NCEP lipoprotein treatment goals: MODERATE RISK:

  • CV risk factors?
  • LDL goal?

  • > 2 risk factors, < 10% ten-year risk
  • < 130 mg/dL

9

NCEP lipoprotein treatment goals: LOWER RISK:

  • CV risk factors?
  • LDL goal?

  • 0-1 risk factors
  • < 160 mg/dL

10

What's the DOC for treating pts w/elevated LDL-C?

Statins

11

Name the 6 different statins.

  1. Lovastatin
  2. Simavastatin
  3. Atorvastatin
  4. Fluvastatin
  5. Rosuvastatin
  6. Pravastatin

12

Statins: MoA?

Inhibits HMG-CoA reductase & triggers SREBP ts factor --> increased LDL-R expression and increased LDL clearance

13

Statins: indications?

High LDLs

14

Statins: toxic/adverse effects?

A. Myalgia/myopathy.

B. ***Rhabdomyolysis***

C. hepatitis.

D. Small risk T2DM.

15

What are some lab and physical signs that a pt has rhabdomyolysis?

  • Fever, malaise, diffuse myalgia and/or tenderness,
  • Marked elevation of serum [CK]
  • Myoglobin present in the urine (dark)

16

When are statins contraindicated?

Severe liver disease, pregnancy (teratogenic)

17

Which statins are metabolized by CYP3A4?

Which statins do not undergo CYP450 metabolism?

Which statins are glucuronidated in the liver?

ASL: atorvastatin, simvastatin, lovastatin

Pravastatin only

All statins

18

CYP3A4 inhibitors ___________ levels of Lovastatin, Simvastatin & Atorvastatin (ASL).

CYP3A4 inhibitors associated with increased risk of what disease?

Increase

Rhabdomyolysis

19

Describe the effect of statins on serum lipids.

v LDL (20-60%)

v TG (10-20%)

^ HDL (5-10%)

20

Give some eg's of CYP3A4 inhibitors.

Eric's red grape kept its clear fluid

  •   Immunosuppressants: cyclosporin &  tacrolimus
  •   Macrolide antibiotics: clarithromycin & erythromycin
  •   Ca2+-channel blockers: diltiazem & verapamil
  •   Anti-arrhythmia drugs: amiodarone
  •   Azole anti-fungals: itraconazole & ketoconazole
  •   HIV protease inhibitors: ritonavir, indinavir & nelfinavir
  •   Anti-coagulants: warfarin

21

Name some eg's of CYP3A4 inducers.

Phen-phen rifled St. John's glowing pink cars.

Phenytoin, Phenobarbitol, Rifampin, St. John's wort, Glucocorticoids, Pioglitazone, Carbamezapine.

Also: barbiturates and thiazolidnediones

22

CYP3A4 inducers ___________ levels of Lovastatin, Simvastatin & Atorvastatin (ASL).

Decrease (and therefore decrease their clinical efficacy)

23

Which of the statins are metabolized by CYP2C9?

Give some eg's of CYP2C9 inhibitors.

(less important than 3A4)

FR (France): fluvastatin, rosuvastatin

Ketoconazole, itraconazole, metronidazole, sulfinpyrazone

24

What transporter do statins use to enter the liver?

OATP2

25

What is the only statin that is FDA-approved for concurrent use w/cyclosporine in cancer tx?

Pravastatin

26

*How does gemfibrozil relate to statin use?

*What is the mech behind this?

  • Strongly associated with an increased risk of statin-induced myopathy and rhabodmyolysis

  1. Inhibits OATP2 transporter-mediated uptake of statins into the liver- can increase statin systemic bioavailability >2X

  2. Inhibits the glucuronidation of statins, which is involved in the metabolism and ultimate excretion of all statins (including Pravastatin)  - can cause an increase in the systemic levels of ALL STATIN drugs.

27

Which is the safest statin to sue when a pt has a weakned liver and why?

Pravastatin (due to dual hepatic/renal elimination)

28

Name the 3 bile acid-binding resins.

Cholestyramine, colestipole, colesevelam

29

Bile acid-binding resins: MoA?

Binds bile acids and prevents reabsorption --> increased cholesterol 7alpha-hydroxylase (rate-limiting enzyme in bile acid synthesis) --> decreased chol --> increased LDL-R --> increased LDL clearance.

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30

When would a bile acid-binding resin be used in combination with a statin?

When instead of a statin?

  • Combo: increase LDL-lowering effect or to allow for lower statin dose to avoid drug interactions
  • When statins are contraindicated (e.g. pregnancy)

31

Bile acid-bindign resins: adverse effects?

  • Generally safe
  • Can increase TG levels in hypertriglyceridemia
  • At high concentrations, Cholestyramine and Colestipol, but not Colesevelam, impair the absorption of the fat soluble vitamins A, D E & K

32

Bile acid-binding resins: contraindications?

TG > 400 mg/dL

Type III Dysbetalipoproteinemia

33

Bile acid-binding resins: effects on serum lipids?

 v LDL (10-25%)

Small increase in TG

34

What's the name of the drug that inhibits cholesterol absorption?

Ezetimibe

35

Ezetimibe: effects on serum lipids?

How is this the same/different compared to bile acid-binding resins?

Effect on serum lipids: v LDL (~18%)

Note: unlike Bile acid-binding resins, Ezetimibe does not raise triglyceride levels

36

Bile acid-binding resins: indications?

High LDL

37

Ezetimibe: indications?

High LDLs

38

Ezetimibe: MoA?

Inhibits intestinal absorption of chol (via NPCL1, small int) --> decreased hepatic chol (therefore reduced VLDLs, LDLs) --> increased LDL-R expression --> increased LDL clearance

39

What are the therapeutic uses for ezetimibe?

  1. Reduces LDL-C in patients with primary hypercholesterolemia
    1. i.e. not completely dependent upon intact LDLR
  2. Can induce a significant further LDL-C lowering effect when combined with a STATIN
    1. Allows the use of a lower STATIN dose to avoid adverse effects

40

Ezetimibe: toxicity?

Generally well-tollerated

41

Name 2 PCSK9 inhibitors.

Alirocumab

Evolocumab

42

PCSK9 inhibitors: MoA?

Inhibits PCSK9 (secreted) --> blocks nl targeting of LDL-R to lysosome --> increased LDL-R expression --> increased LDL clearance

43

PCSK9 inhibitors (alirocumab, evolocumab): indications?

Hetero FH

High LDL not controlled w/statins or statin-intollerant

44

PCSK9 inhibitors: effect on serum lipids?

v LDL (> 50%)

45

Name 2 drugs that are indicated for homozygous familial hypercholesterolemia (FH).

Lomitapide

Mipomersen

46

Lomitapide: MoA?

Inhibits MTP (microsomal triglyceride transfer protein) in both erythrocytes and liver --> decreased production of chylomicrons, VLDL, and LDL

47

Mipomersen: MoA?

Antisense oligonucleotide specific for apoB48/100 --> decreased expression of apoB48/100 --> decreased VLDL & LDLs.

48

Lomitpide: toxicity?

Mipomersen: toxicity?

Hepatotoxicity

Hepatotocity

49

Lomitpide: contraindications?

Mipomersen: contraindications?

Lomitipide: pregnancy

Mipomersen: Mild/mod hepatic impairment

50

Lomitapide: effect on serum lipids?

Mipomersen: effect on serum lipids?

Lomitapide: v chylomicrons, v VLDL, v LDL

Mipomersen: v VLDL, v LDL

51

Elevated serum triglycerides are often a/w what other lipoprotein?

Decrease in HDLs ("good cholesterol")

52

Name all 3 of the drugs whose main action is to lower triglycerides.

Niacin, fibrates (gemfibrozil + fenofibrate)

53

Treatment options for Hypercholesterolemia

1. For moderate hypercholesterolemia with low cardiovascular risk:

Therapeutic lifestyle change

  - Dietary reduction of cholesterol intake

  - Exercise/Weight reduction (improves lipoprotein metabolism)

54

Treatment options for Hypercholesterolemia

2. For severe hypercholesterolemia and/or a high cardiovascular risk

  i.e.   - LDL levels > 190 mg/dL (or > 70 mg/dL with Diabetes)

  - Current clinical evidence of CVD

  - New: 10 yr CVD risk > 7.5% (controversial)

  Answer: 

  Drug therapy is indicated.

  - the initial goal is to reduce LDL - decrease risk of atherosclerosis

  - the initial drug of choice is typically a STATIN

55

Treatment Options for Hypertriglyceridemia:

1. When serum triglycerides are borderline high (150-199 mg/dL)

- Lifestyle change is indicated

- Low fat diet, exercise & cessation of smoking/alcohol

56

Treatment Options for Hypertriglyceridemia:

2. When serum triglycerides are very high (>500 mg/dL)

  - The initial goal is to to prevent pancreatitis by lowering triglyceride levels with either niacin or a fibrate

  - Once triglycerides are <500 mg/dL then any LDL-C goals should be addressed

57

What are 2 other names for niacin?

Nicotinic acid/vitamin B3

58

Niacin: effects on serum lipids?

v TG (30-80%), v LDL (10-20%), ^ HDL (10-30%)

59

Niacin: indications?

High VLDL, high LDL, low HDL

  • Lowers both plasma cholesterol and triglycerides--Useful in the treatment of familial combined hyperlipidemias (­VLDL & ­LDL) and familial dysbetalipoproteinemia (­IDL), i.e. where both cholesterol and triglycerides are elevated.
  • Low HDLs
  • In patients with a history of previous MI, NIACIN has been shown to reduce the incidence of:
    • Re-infarctions, CVAs, overall mortality
  • Combo therapy w/statins (esp. if low HDLs)

60

What's the most effective drug at reducing HDL levels?

Niacin

61

Niacin: MoA? (6)

A. Gi agonist in fat: Decreased lipolysis in adipocytes --> decreased FFA --> decreased VLDL.

B. Inhibits DGAT2 (diacylglycerol transferase, rate-limiting enzyme in hepatic triglyceride synth) --> decreased VLDL synthesis.

C. Decreases hepatic ApoCIII (LPL inhibitor) --> increased LPL --> increased VLDL breakdown --> increased VLDL clearance.

D. Increased apoAI expression --> increased HDL production.

E. Decreased Lp(a) (analog of fibrinogen) --> blocks plasmin formation --> decreased thrombosis.

F. Decreased recruitment of macrophages to atherosclerotic lesions

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62

Niacin: adverse effects?

A. Skin flushing (Tx: NSAIDs prior).

B. Risk of gout.

C. Exacerbates peptic ulcer disease.

D. Risk of hyperglycemia.

E. Hepatitis

63

Niacin: contraindications?

a) Peptic Ulcer disease

b) Patients with a history of gout

c) Used with caution in diabetics

d) Used with caution in patients with impaired liver function

64

Fibrates (fenofibrate/gemfibrozil): indications?

High VLDL, high LDL, low HDL

65

Fibrates (fenofibrate/gemfibrozil): effects on serum lipids?

v TG (40-60%)

v LDL (10-20%)

^ HDL (10-20%)

66

What increases HDLs more, fibrates or niacin?

Niacin

67

Fibrates: MoA?

Ligands for PPARalpha-TF.

A. Decreased ApoC3/increased LPL expression --> increased FA oxidation --> decreased VLDL synthesis --> increased VLDL clearance.

B. increased apoA1 expression --> increased HDL production

(might not need to know this that clearly except beginning and end results)

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68

Fibrates: therapeutic uses?

  • Treatment of hypertriglyceridemia associated with low HDL
    • v triglyceride levels and ^ ­HDL levels
    •   Therapy of choice for patients w/Familial dysbetalipoproteniemia/Type III Hyperlipoproteinemia: ^ plasma triglycerides and IDL/VLDL remnants
  • Treatment of patients with high levels of trigylcerides (>500 mg/dL)
    • --> Risk of pancreatitis (potentially fatal)
  • Long-term fibrate usage proven to reduce the incidence of:
    • Coronary events (22%), CVA (25%), TIA (59%).

69

Fibrates: indications?

High VLDL, low HDL

70

Fibrates: adverse effects?

A. Increased gallstones. (inhibits cholesterol 7a-hydroxylase)

B. Hepatitis.

C. Myopathy.

D. Rhabdomyolysis (very rare, more common w/gemfibrozil). Increased w/high dose statin!

71

What is the general mechanism behind fibrates drug interactions?

Strong protein binders, can displace others

72

What are some of the drug interactions a/w fibrate

(Strong protein binders--increase serum conc of other drugs)

^ warfarin --> ^ risk of bleeding.

^ sulfonylureas --> (stimulate insulin) ^ hypoglycemia.

Statin interaction: ^[statins] --> ^rhabdomyolysis, esp. gemfibrozil.

73

Explain the mechanism behind fibrates interaction w/statins.

Are any statins not affected?

Which of the fibrates is a/w this effect?

Inhibit OATP2/glucuronidation.

Affects ALL statins

Gemfibrozil (therefore use fenofibrate when combining w/statins!!)

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74

Fibrates: contraindications?

1. Pregnant

2. Severe hepatic disfunction

3. Severe renal dysfunction (both fibrates renall excreted--a/w ^ risk rhabdomyolysis)

4. Pre-existing GB disease (inhibition of cholesterol 7a-hydroxylase gene expression)

75

What lipids are in fish oils?

Omega-3 long chain polyunsaturated fatty acids

Ethyl esters of eicosapentaenoic acid & Docosahexaenoic acid

76

Fish oils: MoA?

•Mechanism of action is unclear, but appears to involve inhibiting the expression of genes involved in hepatic triglyceride synthesis

• Also posses anti-inflammatory activity- acts via GPCR expressed on macrophages

77

Fish oils: effects on serum lipids?

Lowers TGs by 30-50%

Minor increase in HDL

Can lower LDLs in some people