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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.

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