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HLD drugs Flashcards

1
Q

High triglycerides can eventually result in what condition?

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

A

Pancreatitis

> 500 mg/dL

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2
Q

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

A
  • Desireable: < 100 mg/dL
  • Borderline: 100-159 mg/dL
  • High: >190 mg/dL
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3
Q

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

A
  • Men: > 40 mg/dL
  • Women: > 50 mg/dL
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4
Q

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

A
  • Desirable: < 150 mg/dL
  • Borderline: 150-199 mg/dL
  • High: > 200 mg/dL (> 500 very high)
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5
Q

NCEP lipoprotein treatment goals: VERY HIGH RISK:

  • CV risk factors?
  • LDL goal?
A
  • Current CHD + other factors
  • < 70 mg/dL
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6
Q

NCEP lipoprotein treatment goals: HIGH RISK:

  • CV risk factors?
  • LDL goal?
A
  • Previous CHD, diabetes, > 2 risk factors
  • < 100 mg/dL (optional < 70)
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7
Q

NCEP lipoprotein treatment goals: MODERATELY HIGH RISK:

  • CV risk factors?
  • LDL goal?
A
  • > 2 risk factors. 10-20% ten-year risk
  • < 130 mg/dL (optional < 100 mg/dL)
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8
Q

NCEP lipoprotein treatment goals: MODERATE RISK:

  • CV risk factors?
  • LDL goal?
A
  • > 2 risk factors, < 10% ten-year risk
  • < 130 mg/dL
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9
Q

NCEP lipoprotein treatment goals: LOWER RISK:

  • CV risk factors?
  • LDL goal?
A
  • 0-1 risk factors
  • < 160 mg/dL
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10
Q

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

A

Statins

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11
Q

Name the 6 different statins.

A
  1. Lovastatin
  2. Simavastatin
  3. Atorvastatin
  4. Fluvastatin
  5. Rosuvastatin
  6. Pravastatin
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12
Q

Statins: MoA?

A

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

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13
Q

Statins: indications?

A

High LDLs

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14
Q

Statins: toxic/adverse effects?

A

A. Myalgia/myopathy.

B. ***Rhabdomyolysis***

C. hepatitis.

D. Small risk T2DM.

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15
Q

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

A
  • Fever, malaise, diffuse myalgia and/or tenderness,
  • Marked elevation of serum [CK]
  • Myoglobin present in the urine (dark)
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16
Q

When are statins contraindicated?

A

Severe liver disease, pregnancy (teratogenic)

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17
Q

Which statins are metabolized by CYP3A4?

Which statins do not undergo CYP450 metabolism?

Which statins are glucuronidated in the liver?

A

ASL: atorvastatin, simvastatin, lovastatin

Pravastatin only

All statins

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18
Q

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

CYP3A4 inhibitors associated with increased risk of what disease?

A

Increase

Rhabdomyolysis

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19
Q

Describe the effect of statins on serum lipids.

A

v LDL (20-60%)

v TG (10-20%)

^ HDL (5-10%)

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20
Q

Give some eg’s of CYP3A4 inhibitors.

A

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
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21
Q

Name some eg’s of CYP3A4 inducers.

A

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

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

Also: barbiturates and thiazolidnediones

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22
Q

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

A

Decrease (and therefore decrease their clinical efficacy)

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23
Q

Which of the statins are metabolized by CYP2C9?

Give some eg’s of CYP2C9 inhibitors.

(less important than 3A4)

A

FR (France): fluvastatin, rosuvastatin

Ketoconazole, itraconazole, metronidazole, sulfinpyrazone

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24
Q

What transporter do statins use to enter the liver?

A

OATP2

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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.
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%) ## Footnote 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
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. ## Footnote 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)
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!!_)
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

Pharm (32 decks)

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