Atherosclerosis Drugs Flashcards
What is the mechanism of Atorvastatin/Lovastatin/Simvastatin?
Competitive inhibitors for active site of HMG Co-A reductase (structural analog of HMG CoA intermediate)
Pharmacokinetics of Atorvastatin/Lovastatin/Simvastatin?
- Extensive first pass metabolism by liver (limits systemic bioavailability)
- High plasma protein binding
- Variable half life
How is the statins metabolized?
CYB3A4
How are Lovastatin and Simvastatin metabolized?
Administered as inactive lactones that must be transformed in liver. Prodrugs.
What are the adverse effects of Statin drugs?
- Usually well tolerated
- Myopathy (symmetrical,proximal)
- Rhabdomyolysis (breakdown of muscle fibers)
- GI/liver
When are statins contraindicated?
Pregnant Lactating Likely to be pregnant Active liver disease Hypersensitivity
What are the clinical uses of statins?
First line therapy in Hypercholesterolemia when at risk for MI
What is the lipoprotein profile or statins?
TG - decrease 20-55%
LDL - decrease 20-55%
HDL - increase 5-10%
What is the bile acid binding drug?
Cholestyramine
What is the mechanism of Cholestyramine?
Highly positively charged that binds bile acids –> depletes bile acid pool and hepatic bile acid synthesis increases –> hepatic cholesterol declines and stimulates production of LDL receptors
What are the pharmacokinetics of Cholestyramine?
- Not absorbed! (no systemic S/E)
- Administered as chloride salt/insoluble in water
What are adverse effects of Cholestyramine?
Constipation/bloating
Interferes with absorption of other drugs
Modest increase in TG/with time returns to baseline
What are C/I of Cholestyramine?
Hypercholesterolemia
Increased TG
What are clinical uses of Cholestyramine?
Hypercholesterolemia
Second line if statin does not lower LDL-C levels
Recommended for patients 11-20 years
What is lipoprotein profile of Cholestyramine?
TG - significant increase when levels increased to begin with
LDL - decrease by 12-25%
HDL - increase by 4-5%
What is the mechanism of Niacin?
Inhibits FFA mobilization in adipose tissue
Decreases synthesis of VLDL, TG in liver
Inhibits uptake of HDL
What are the pharmacokinetics of Niacin?
Oral administration
3 different formulations
Much greater dose needed for lowering TG than those used as vitamin
What are adverse effects of Niacin?
Intense cutaneous flush (treat with NSAIDs)
GI effects
Elevated liver enzymes
Hyperurecemia
Increases glucose levels/insulin resistance
What are C/I of Niacin?
Peptic ulcer
Hepatic disease (MAJOR)
Gout
Diabetes
What are clinical uses of Niacin?
Hypercholesterolemia
Hypertriglyceridemia
Reduces Lp(a)
What is lipoprotein profile of Niacin?
TG - decreased 35-50%
LDL - decreased 25%
HDL - increased 15-30%
Lp(a) - reduced 40%
What is the mechanism of action of Ezetimibe?
It inhibits protein transporter Niemann Pick C10 like protein to cause decreased rate of cholesteryl ester incorporation into chylomicrons –> causes increased expression of hepatic LDL receptor
What are the pharmacokinetics of Ezetimibe?
Oral administration
Metabolized to active metabolite
22 hour half life
What are the adverse effects of Ezetimibe?
Normally well tolerated
S/E increase if combined with other drugs
What are the clinical uses of Ezetimibe?
Hypercholesterolemia
Combined with statins - unsure if helpful
What is the lipoprotein profile of Ezetimibe?
Modest decreases in TG, LDL and increases in HDL
What are the drugs of choice for Hypercholesterolemia?
Statins - HMG CoA Reductase inhibitors
Bile acid resins - younger patient age range, add on to statins
Ezetimibe - safe as mono therapy
Niacin - patient compliance problems,
What are the drugs of choice for Hypertriglyceridemia?
Gemfibrozil/Fenofibrate
Niacin
Omega 3 FA
What are two examples of Fibric Acid?
Gemfibrozil and Fenofibrate
What is the mechanism of action of Gemfibrozil and Fenofibrate?
They are ligands for a nuclear transcription regulator called Peroxisome proliferator activated receptor that regulates gene expression and causes decreased TG, decreased inflammation, increased HDL synthesis and Increased Lipoprotein Lipase
What are the pharmacokinetics of Gemfibrozil and Fenofibrate?
Oral administration, plasma protein binding, half life varies, Fenofibrate is a prodrug
What are the adverse effects of Gemfibrozil and Fenofibrate?
Well tolerated
GI symptoms
Hematological
Increased CK/renal failure when combined with statin
When are Fenofibrate and Gemfibrozil C/I?
Renal impairment (esp Fenofibrate)
What are the clinical uses of Fenofibrate and Gemfibrozil?
Patients with high TGs and low HDL (associated with metabolic syndrome and DM2)
What are the effects of Omega 3 FA?
Lipid lowering effects; inhibits lipogenesis, stimulates B oxidation, phospholipid synthesis and apolipoprotein B degradation
What is the clinical use for Omega 3 FA?
Adjunct to diet therapy in treatment of hypertriglyceridemia
What does the protein PCSK9 do?
It degrades the LDL receptor
What does the MTP protein do?
Transfers lipids between membrane vesicles; chaperone for biosynthesis of apoB containing TG rich lipoproteins (VLDL, chylomicrons)
What would be the clinical use for a MTP inhibitor?
Homozygous Familiar Hypercholesterolemia
What is the protein apo B 100?
It is an apolipoprotein essential for LDL-C and VLDL. IT helps LDL bind to it’s receptor on hepatocytes
What would be the clinical use for an apoB inhibitor?
Homozygous Familial Hypercholesterolemia
