Atherosclerosis Drugs

Question 1

What is the mechanism of Atorvastatin/Lovastatin/Simvastatin?

Answer 1

Competitive inhibitors for active site of HMG Co-A reductase (structural analog of HMG CoA intermediate)

Question 2

Pharmacokinetics of Atorvastatin/Lovastatin/Simvastatin?

Answer 2

• Extensive first pass metabolism by liver (limits systemic bioavailability)
• High plasma protein binding
• Variable half life

Question 3

How is the statins metabolized?

Answer 3

CYB3A4

Question 4

How are Lovastatin and Simvastatin metabolized?

Answer 4

Administered as inactive lactones that must be transformed in liver. Prodrugs.

Question 5

What are the adverse effects of Statin drugs?

Answer 5

• Usually well tolerated
• Myopathy (symmetrical,proximal)
• Rhabdomyolysis (breakdown of muscle fibers)
• GI/liver

Question 6

When are statins contraindicated?

Answer 6

Pregnant
Lactating 
Likely to be pregnant
Active liver disease
Hypersensitivity

Question 7

What are the clinical uses of statins?

Answer 7

First line therapy in Hypercholesterolemia when at risk for MI

Question 8

What is the lipoprotein profile or statins?

Answer 8

TG - decrease 20-55%
LDL - decrease 20-55%
HDL - increase 5-10%

Question 9

What is the bile acid binding drug?

Answer 9

Cholestyramine

Question 10

What is the mechanism of Cholestyramine?

Answer 10

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

Question 11

What are the pharmacokinetics of Cholestyramine?

Answer 11

• Not absorbed! (no systemic S/E)

- Administered as chloride salt/insoluble in water

Question 12

What are adverse effects of Cholestyramine?

Answer 12

Constipation/bloating
Interferes with absorption of other drugs
Modest increase in TG/with time returns to baseline

Question 13

What are C/I of Cholestyramine?

Answer 13

Hypercholesterolemia

Increased TG

Question 14

What are clinical uses of Cholestyramine?

Answer 14

Hypercholesterolemia
Second line if statin does not lower LDL-C levels
Recommended for patients 11-20 years

Question 15

What is lipoprotein profile of Cholestyramine?

Answer 15

TG - significant increase when levels increased to begin with
LDL - decrease by 12-25%
HDL - increase by 4-5%

Question 16

What is the mechanism of Niacin?

Answer 16

Inhibits FFA mobilization in adipose tissue
Decreases synthesis of VLDL, TG in liver
Inhibits uptake of HDL

Question 17

What are the pharmacokinetics of Niacin?

Answer 17

Oral administration
3 different formulations
Much greater dose needed for lowering TG than those used as vitamin

Question 18

What are adverse effects of Niacin?

Answer 18

Intense cutaneous flush (treat with NSAIDs)
GI effects
Elevated liver enzymes
Hyperurecemia
Increases glucose levels/insulin resistance

Question 19

What are C/I of Niacin?

Answer 19

Peptic ulcer
Hepatic disease (MAJOR)
Gout
Diabetes

Question 20

What are clinical uses of Niacin?

Answer 20

Hypercholesterolemia
Hypertriglyceridemia
Reduces Lp(a)

Question 21

What is lipoprotein profile of Niacin?

Answer 21

TG - decreased 35-50%
LDL - decreased 25%
HDL - increased 15-30%
Lp(a) - reduced 40%

Question 22

What is the mechanism of action of Ezetimibe?

Answer 22

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

Question 23

What are the pharmacokinetics of Ezetimibe?

Answer 23

Oral administration
Metabolized to active metabolite
22 hour half life

Question 24

What are the adverse effects of Ezetimibe?

Answer 24

Normally well tolerated

S/E increase if combined with other drugs

Question 25

What are the clinical uses of Ezetimibe?

Answer 25

Hypercholesterolemia | Combined with statins - unsure if helpful

Question 26

What is the lipoprotein profile of Ezetimibe?

Answer 26

Modest decreases in TG, LDL and increases in HDL

Question 27

What are the drugs of choice for Hypercholesterolemia?

Answer 27

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,

Question 28

What are the drugs of choice for Hypertriglyceridemia?

Answer 28

Gemfibrozil/Fenofibrate Niacin Omega 3 FA

Question 29

What are two examples of Fibric Acid?

Answer 29

Gemfibrozil and Fenofibrate

Question 30

What is the mechanism of action of Gemfibrozil and Fenofibrate?

Answer 30

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

Question 31

What are the pharmacokinetics of Gemfibrozil and Fenofibrate?

Answer 31

Oral administration, plasma protein binding, half life varies, Fenofibrate is a prodrug

Question 32

What are the adverse effects of Gemfibrozil and Fenofibrate?

Answer 32

Well tolerated GI symptoms Hematological Increased CK/renal failure when combined with statin

Question 33

When are Fenofibrate and Gemfibrozil C/I?

Answer 33

Renal impairment (esp Fenofibrate)

Question 34

What are the clinical uses of Fenofibrate and Gemfibrozil?

Answer 34

Patients with high TGs and low HDL (associated with metabolic syndrome and DM2)

Question 35

What are the effects of Omega 3 FA?

Answer 35

Lipid lowering effects; inhibits lipogenesis, stimulates B oxidation, phospholipid synthesis and apolipoprotein B degradation

Question 36

What is the clinical use for Omega 3 FA?

Answer 36

Adjunct to diet therapy in treatment of hypertriglyceridemia

Question 37

What does the protein PCSK9 do?

Answer 37

It degrades the LDL receptor

Question 38

What does the MTP protein do?

Answer 38

Transfers lipids between membrane vesicles; chaperone for biosynthesis of apoB containing TG rich lipoproteins (VLDL, chylomicrons)

Question 39

What would be the clinical use for a MTP inhibitor?

Answer 39

Homozygous Familiar Hypercholesterolemia

Question 40

What is the protein apo B 100?

Answer 40

It is an apolipoprotein essential for LDL-C and VLDL. IT helps LDL bind to it's receptor on hepatocytes

Question 41

What would be the clinical use for an apoB inhibitor?

Answer 41

Homozygous Familial Hypercholesterolemia