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
Niacin: adverse effects?
A. Skin flushing (Tx: NSAIDs prior).
B. Risk of gout.
C. Exacerbates peptic ulcer disease.
D. Risk of hyperglycemia.
E. Hepatitis
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
Fibrates (fenofibrate/gemfibrozil): indications?
High VLDL, high LDL, low HDL
Fibrates (fenofibrate/gemfibrozil): effects on serum lipids?
v TG (40-60%)
v LDL (10-20%)
^ HDL (10-20%)
What increases HDLs more, fibrates or niacin?
Niacin
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)
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%).
- v triglyceride levels and ^ HDL levels
- Therapy of choice for patients w/Familial dysbetalipoproteniemia/Type III Hyperlipoproteinemia: ^ plasma triglycerides and IDL/VLDL remnants
- --> Risk of pancreatitis (potentially fatal)
- Coronary events (22%), CVA (25%), TIA (59%).
Fibrates: indications?
High VLDL, low HDL
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!
What is the general mechanism behind fibrates drug interactions?
Strong protein binders, can displace others
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.
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!!)
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)
What lipids are in fish oils?
Omega-3 long chain polyunsaturated fatty acids
Ethyl esters of eicosapentaenoic acid & Docosahexaenoic acid
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
Fish oils: effects on serum lipids?
Lowers TGs by 30-50%
Minor increase in HDL
Can lower LDLs in some people
