The Pharmacology Of Drugs For Hyperlipoproteinemias

Front 1

Lets start with the basics - name the prototype:

1. Nicotinic acid preparations

2. Fibric Acids

3. Bile Acid Binding Resins

4. Statins

Back 1

1. Niacin (vitamin B3)

2. Gemfibrozil

3. Cholestyramine

4. Atorvastatin

Front 2

General rationale for the use drugs in the treatment of Hyperlipoproteinemias

Back 2

1. Decrease risk of cardiovascular morbidity and mortality

2. Decrease risk of pancreatitis

Front 3

First choice drug(s) used for:

1. Decreasing risk of cardiovascular morbidity and mortality

2. Decreasing risk of pancreatitis

Back 3

1. statins

2. fibrates; others: niacin, omegaT3 fish oils (EHA,DHA)

Front 4

Effects of nicotinic acid on serum lipoproteins?

Back 4

1. Decreases triglycerides and LDL

2. Increases HDL cholesterol

Front 5

How does niacin decrease triglycerides and LDL?

Back 5

–Decreases fatty acid release from adipose tissue by action on GPCR
–Decreases hepatc VLDL synthesis and release which effectively decreases LDL and Lipoprotein(a)

Front 6

Are niacins used in combination with statins?

Back 6

latest evidence discourages combination with statins except for special indications

Front 7

How does niacin increase HDL?

Back 7

Decreases ApoA1 hepatic uptake

Front 8

Is niacin the drug of choice in a pt with abnormalities in serum triglycerides?

Back 8

No, Fibrates are better

Front 9

Side effects of niacin?

Back 9

hepatotoxicity

cutaneous flush

GI

Front 10

What mediates the cutaneous flush in niacin toxicity?

Back 10

prostaglandins

Front 11

1. What is the mechanism of action of gemfibrozil?

2. What are it's major effects?

Back 11

1. Activates the transcription factor PPARα

2. Decreases serum triglycerides

Increases LDL receptor expression

Increase serum HDL cholesterol

Front 12

1. How does gemfibrozil decrease serum triglycerides?

2. How does gemfibrozil increase serum HDL?

Back 12

1. Increases lipoprotein lipase activity and FA oxidation; decreases VLDL secretion from the liver (may cause an increase in LDL)

2. Increases Apo A1and 2 gene expression

Front 13

Indication(s) for fibrates?

Back 13

severe hypertriglyceridemia to reduce risk of pancreatitis

also used to increase HDL levels

Front 14

Side effects of fibrates?

Back 14

Increases risk of statin myopathy and rhabdomyolysis

dyspepsia and galstones

Front 15

How do fibrates increase risk of myopathy

Back 15

Gemfibrozil and it's major metabolite inhibits certain P450 enzymes and OATP which increases AUC of other drugs, ie statins

Front 16

If fibrates and statins are prescribed concurrently, it is recommended that the serum _______________________ be monitored every several months.

Back 16

If fibrates and statins are prescribed concurrently, it is recommended that the serum creatine kinase (a marker of muscle inflammation or necrosis) be monitored every several months.

Front 17

Cholestyramine's effects on serum lipoproteins?

Back 17

Increase hepatic expression of LDL receptors

Increase clearance of LDL cholesterol from plasma (reduces LDL levels)

Front 18

Cholestyramine's mechanism of action?

Back 18

Quaternary ammonium that binds negative bile salts to block their reabsoprtion.

This causes more hepatic cholesterol to be converted to bile acids which depletes cholesterol stores.

Front 19

Indication for cholestyramine?

Back 19

Used sparingly as a second-line agent with statins

Front 20

Sides effects of cholestyramine

Back 20

1. Increases serum triglycerides

2. GI side effects:

-constipation

-impaired absorption of fat

-cant be taken with anionic drugs (warfarin, propranolol, digoxin, thyroid hormone)

Front 21

Effect of Ezetimibe on lipoproteins

Back 21

Reduces serum LDL by 20%

Front 22

Ezetimibe mechanism of action?

Back 22

competitively inhibits an apical transporter in the small intestine thats responsible for facilitating the absorption of cholesterol

reduces chylomicron production = reduced cholesterol delivery to liver

Front 23

Clinical use of ezetimibe?

Problems with ezetimibe (2)?

Back 23

Used in combination with statins for additive effects.

Problems:

1. did not reduce plaque size and may increase cancer risk

2. was less effective than niacin-statin combination

Front 24

Statins effects on lipoproteins?

Back 24

Decrease LDL

Increase HDL

Decrease triglycerides

Front 25

Statins mechanism of action (3 steps)

Back 25

1. potent competitive inhibitors of hepatic HMG-CoA reductase

2. decreased formation of intermediates in cholesterol synthesis pathway

3. transcriptional effect on the LDL receptor gene

Front 26

What effect does inhibiting HMG-CoA reductase have (4 steps)?

Back 26

1. Decrease in hepatic cholesterol increases activity of a protease
2. Protease releases sterol-regulatory-element binding protein (SREBP) from ER
3. SREBP interacts with promoter of LDL receptor gene
4. More LDL receptor is synthesized and inserted into hepatic membrane

Front 27

Indication for statin use in primary prevention (4 criteria)?

Back 27

Statins are used as primary prevention in pts:

-no history of CV disease

-age 40-75

- >7.5% 10yr risk score

-LDL-C 70-189 mg/dL

Front 28

Indication for statin use in secondary prevention?

Back 28

history of CV event (MI, stroke, stable or unstable angina, peripheral artery disease, TIA, or coronary or other arterial revascularization)

Front 29

When are statins indicated for a pt who is >/= to 21 y/o

Back 29

LDL > 190

Front 30

When are statins indicated for a pts with diabetes

Back 30

Pts who are 40-75 with LDL 70-189

Front 31

Toxicities of Statins?

Back 31

1. contraindicated in pregnancy

2. Increase in hepatic enzymes

3. Myopathy

Front 32

Blood test that is a marker for statin myopathy?

Back 32

-creatine kinase

Front 33

Risk of statin myopathy is increased by?

Back 33

– genotype for rate-limiting enzyme in creatine synthesis
– higher statin Cp

Front 34

What can cause higher stating Cp?

Back 34

• dose
• drug interactions (gemfibrozil, CYP inhibitors)
• specific SNP in genotype of an OATP that transports statin into hepatocyte

Front 35

Azole and HIV protease inhibitors effect on statins?

Back 35

Inhibit CYP450 so increase levels of some statins including atorvastatin