Dyslipidemia Pharmacology

Question 1

Define Dyslipidemia

Answer 1

Hypercholeserolemia
Hyper TG
Low HDL

Question 2

Dyslipidemia is a major cause of

Answer 2

increased atherogenic risk and atherosclerosis-associated conditions: ischemic HD, CVD, PVD

Question 3

Dyslipidemia is recognized as

Answer 3

risk facotr for CVD and lipid-lowering thearpy is very beneficial

Question 4

Primary goal of drug therapy of dyslipidemia

Answer 4

Reduce LDL levels

Question 5

Other goals of drug therapy of dyslipidemia

Answer 5

Elevate HDL and reduce TG levels

Question 6

Acetyl CoA is used to form what via what?

Answer 6

Mevalonic Acid via HMGCoA reductase

RATE LIMITING STEP

Question 7

Cholesterol is used in the making of?

Answer 7

steroid hormones like glucocorticoids, mineralcorticoids and sex hormones
Cell membranes
Bile acids

Question 8

Statins

Answer 8

Mevastatin (first)
Lovastatin (most common)
Simvastatin
Pravastatin
Fluvastatin
Atorvastatin (Lipitor)
Rosuvastatin (no generic)
Pitavastatin

Question 9

Statin structure is based on?

Answer 9

Trying to find a compound that would inhibit the rate limiting step

Question 10

Statin MOA

Answer 10

competitive inhibitors of HMGCoA reductase and block synthesis of cholesterol

Question 11

Effects of Statins

Answer 11

Synthesis is blocked in the liver –> increased LDL receptors –> increased removal of LDL from blood –> reduction of LDL levels

Question 12

Statin + TGs

Answer 12

Leads to increased LDL receptors which leads to increased removal of LDL precursors (IDL, VLDL) which reduces TGs and the overall reduction of cholesterol leads to decreased synthesis of VLDL which decreases TGs

Question 13

What else can statins do?

Answer 13

Increase HDL by 7.5%

Question 14

Statin Pleiotropic Effects

Answer 14

Improve endothelial function and enhanced NO production
Down regulate AT1 receptor
Increased plaque stability (inhibit SMC proliferation and migration and inhibit monocyte infiltration)
Anti-inflammatory (Athero)
Antioxidant (CV)
Anti-platelet effect (Clots)

Question 15

Define pleiotropic

Answer 15

Beneficial but have nothing to do with lipid lowering effects of statins

Question 16

Statins PK

Answer 16

Poor bioavailability
Large first pass effect
Excreted by liver and eliminated in feces

Question 17

Pro-drug Statins?

Answer 17

Lovastatin and Simvastatin

Question 18

Provastatin CYP

Answer 18

NOT cyp

3 day half life

Question 19

Fluvastatin CYP

Answer 19

75% 2C9

Question 20

CYP3A4

Answer 20

Atorvastatin
Lovastatin
Simvastatin

Question 21

Inhibitors of 3A4

Answer 21

Clarithro
Erthro
Keto
Itra
HIV PIs
Grapefruit juice

Question 22

Inducers of 3A4

Answer 22

Rifampin

Efavirenz

Question 23

Inhibitors of 2C9

Answer 23

Gemfibrozil which is the enzyme that metabolizes Fluvastatin!!!

Question 24

Statin AEs

Answer 24

Hepatotoxicity
Myopathy –> rhabdomyolysis (breakdown of muscle fibers)
Cognitive effects (reversible)
Hyperglycemia (increase glc and A1c; but benefit still outweighs the risk in DM pts)
TSH (falsely lowers the TSH levels

Question 25

Rhabdomyolysis

Answer 25

Can be indicated by elevated CK levels but not always

Question 26

AEs in statins are

Answer 26

concentration dependent

Question 27

Statins are cautioned with:

Answer 27

``` Drug combinations Hepatic/renal dysfunction Perioperative period Advanced age Multisystem disease Small body size Gemfibrozil ```

Question 28

Gemfibrozil does what?

Answer 28

Inhibits uptake of active hydroxy acid forms of statins into hepatocytes and their glucuronidation (double plasma concentration of statins

Question 29

Bile acid sequestrants

Answer 29

Cholestyramine Colestipol Colesevelam

Question 30

Bile acid sequestrants are the

Answer 30

safest bc they are not absorbed from the intestine

Question 31

What is the precursor of bile acids?

Answer 31

Cholesterol

Question 32

Bile acid sequestrants MOA

Answer 32

BAS have + charged and bind - charged bile acids --> not absorbed in the intestines --> eliminated in feces --> increase synthesis of bile acids (using cholesterol) --> decreased cholesterol --> increased LDL receptors and decreased LDL levels --> reduction of LDL

Question 33

Bile acid sequestrants effects on lipid profile

Answer 33

Decreased LDL (max in 1-2 weeks) Reduced cholesterol which upregulates HMG-CoA reductase (good with a statin) HyperTGs Elevated HDL by 4-5%

Question 34

Adverse effects

Answer 34

HyperTG Interfere with absorption of sterols (digitalis), acidic drugs, fat soluble vitamins) May cause constipation

Question 35

Niacin activity

Answer 35

Decreases TGs by 35-45% and LDL by 20-30% | BEST: Increases HDL by 30-40%

Question 36

Niacin MOA

Answer 36

Niacin + receptors in adipocytes --> reduced cAMP --> decreased breakdown of TGs --> Decreased FFA --> Decreased TG synthesis --> Decreased VLDL and reduction of LDL

Question 37

Niacin MOA for HDL increase

Answer 37

Reduced hepatic clearance of apoA-I

Question 38

Niacin Adverse Reactions

Answer 38

Hepatotocitiy Insulin resistance Elevated uric acid

Question 39

Fibric acid derivatives (PPARalpha agonists)

Answer 39

Clofibrate Gemfibrozil Fenofibrate

Question 40

Fibric acid derivatives (PPARα agonists) MOA

Answer 40

Fibrate + PPARα leads to increased FA oxidation, increased LPL synthesis which leads to increased clearance of TG rich proteins and decreased expression of apoC-III which increases clearance of VLDL All of which decrease TG levels

Question 41

Fibric acid derivatives (PPARα agonists) MOA + HDL

Answer 41

Fibrate + PPARα Leads to increase expression of apoA-I and apoA-II which elevated HDL levels

Question 42

Fibric acid derivatives (PPARα agonists) effects of lipid profile in Mild hyperTG

Answer 42

50% decrease in TG 15% increase in HDL LDL unchanged

Question 43

Fibric acid derivatives (PPARα agonists) effects of lipid profile in High HyperTG

Answer 43

50% TG reduction | LDL 10-30% INCREASE (YIKES)

Question 44

Fibric acid derivatives (PPARα agonists) are drug of choice in:

Answer 44

SEVERE hyperTG and chylomicronemia syndrome

Question 45

Fibric acid derivatives (PPARα agonists) caution in combo with:

Answer 45

``` Oral anticoagulants (higher concentration) Statins with gemfibrozil ```

Question 46

Ezetimibe is a

Answer 46

dietary cholesterol uptake inhibitor

Question 47

Ezetimibe causes ____ but doesn't effect ____

Answer 47

synthesis in cholesterol in liver | TG absorption

Question 48

Ezetimibe MOA

Answer 48

Reduces cholesterol absorption --> decreased chylomicron formation --> increased LDL receptor expression --> increased clearance of LDL

Question 49

Ezetimibe effects on lipid panel

Answer 49

15-20% LDL reduction 5% TG reduction 1-2% HDL increase

Question 50

Omega-3-acid ethyl esters

Answer 50

Lovaza (Omacor) | Vascepa (icosapent)

Question 51

Omega-3-acid ethyl esters Use

Answer 51

Adjunct to reduce TG levels (hyperTG - >500)

Question 52

Omega-3-acid ethyl esters MOA

Answer 52

Inhibit acyl CoA acyltransferase Increase oxidation of lipids in liver Decreased lipogenesis Increased LPL activity

Question 53

Difference between Lovaza and Vascepa

Answer 53

L: increase LDL V: decreased LDL

Question 54

PCSK9

Answer 54

Induces degradation of LDL receptors --> we would want to block this in a future drug!!