Lipid Lowering

Question 1

Blocks conversions of cholestend to bile acids

Answer 1

Bile and resins

Question 2

Lowers plasma LDL by indirectly increasing rate of LDL clearance from plasma

Answer 2

Bile acid resin

Question 3

What enzyme does bile acid block and with what effect

Answer 3

Inhibits 7 alpha hydroxylase

Blocks conversion of cholesterol to bile acids

Question 4

What is the other mechanism of action of bile acids in the GI tract

Answer 4

Bind major bile acids and increase their fecal excretion

Question 5

What is the effect of bile acids MOA in the GI

Answer 5

Net decrease of bile acids returned to the liver

Removing the negative inhibition of 7 alpha hydroxylase to make more bile acids from cholesterol

Question 6

What is the effect of hepatic cholesterol reduction due to bile acid production

Answer 6

Increase in LDL receptor expression

Increase in uptake of plasma LDL

HMG-COA reductase induction

Increased cholesterol biosynthesis

Question 7

What is the crosslinking agent of bile acid resins

Answer 7

Positively charge groups with amines acting as a binding site for bill acids

Question 8

What are ADR of bile acids

Answer 8

Constipation is common

Increased frequency of loose stool

Hypoprothrombonemia (impaired clotting)

Bleeding events since bile acids bind Vit K

Question 9

What are bile acids drug interaction

Answer 9

Bind acidic compounds and can decrease oral absorption

Question 10

What medication is of major concern with bile acids therapy and vit K

Answer 10

Warfarin. Vitamin K is important concern can induce supratherapeutic INR

Question 11

How is drug interaction avoided for patients on bile acid resins

Answer 11

Take 1 hour before or 4 hours after bile acids.

Question 12

What is the mechanism of action of statins and why

Answer 12

Block HMG- COA reductase because it is the rate limiting step in cholesterol biosynthesis

Question 13

Blocking of HMG-COA reductase by statins lead to what effect

Answer 13

Decreased cholesterol, increasing expression of HMG-COA reductase and LDL receptors

Question 14

What are other mechanism of action of statins

Answer 14

Inhibit cholesterol synthesis

Enhance LDL uptake

Recheck VLDL precursors

Question 15

What is the primary mechanism of lowering LDL levels with statins

Answer 15

Enhanced LDL receptor expression

Question 16

What are the natural or semi-synthetic statins

Answer 16

Lovastatin (mushroom)

Simvastatin

Pravastatin (bacteria)

Question 17

Which two natural or semi-synthetic are inactive produng form and why

Answer 17

Lovastatin and Simvastatin due to Lactone ring

Question 18

Metabolized by CYP3A4

Answer 18

Simvastatin and lovastatin

Question 19

Not metabolized by 3A4

Answer 19

Pravastatin

Question 20

What are the synthetic statins

Answer 20

Fluvastatin - Lescol

Atorvastatin - Lipitor

Pitavastatin - Livalo

Rosuvastatin- Crestor

Question 21

2C9 (70%) and 3A4 (20%)

Answer 21

Fluvastatin

Question 22

Mostly 3A4

Answer 22

Atorvastastin

Question 23

2C9 and lactonization

Answer 23

Pitavastatin

Question 24

Partly 2C9 (10%)

Answer 24

Rosuvastatin

Question 25

What are the toxicity of statins

Answer 25

GI Rhabdomylosis Avoid in pregnancy and lactation due to muscle effect Mild increase in creatnine phosphokinase Increased myopathy

Question 26

What drug class increase myopathy when given with statins

Answer 26

3A4 inhibitors

Question 27

3A4 inhibitors

Answer 27

Cyclosporine Azole of antifungal macrolides: erythromycin and clarithromycin HIV protease inhibitors Nefazodone Grapefruit juice Verapamil

Question 28

How does statin induce myoporthy

Answer 28

Blocking mevalonate production, decreases ubiquinones (coenzyme Q) required for electron transfer through mitochondrial membrane

Question 29

What is PCSK9

Answer 29

Protein that bind to LDL receptors promoting its degradation and increases plasma levels of circulating LDL

Question 30

What are medication is used to lower lipid in this pathway

Answer 30

PCSK9 inhibitor

Question 31

What medication are classified under PCSK9 intribitors

Answer 31

Evolocumab, Repatha Alirocumab, Praluent

Question 32

What type of drugs are PCSK9

Answer 32

Monoclonal antibodies that binds to circulating PCSK9

Question 33

What is the effect of PCSK9 binding

Answer 33

Increase in LDL receptors and LDL-Cholesterol clearance in plasma

Question 34

How is PCSK9-Inhibitors administered

Answer 34

2-4 weeks injections

Question 35

What patient group is placed on PCSK-9 inhibitors

Answer 35

LDL:500-600 mg/dL Patient with hypertipidemia or hypercholestrolemia

Question 36

Which medication is a cholesterol transport inhibitor

Answer 36

Ezetimibe (Zetia)

Question 37

What is the drug class of ezetimibe

Answer 37

Azetidinones

Question 38

What is the effect of ezetimibe

Answer 38

Inhibits cholesterol absorption Decreasing cholesterol and increasing its brosynthests Causing overall lowering of LDL

Question 39

True or false: ezetimibe interfers with absorption of other compounds

Answer 39

False

Question 40

Where is ezetimbe metabolized

Answer 40

Intestinal wall and liver

Question 41

What is the major active metabolite of ezetimibe

Answer 41

Phenolic glucuronide

Question 42

How is the glucuronide metabolite metabolized

Answer 42

Excreted in bile and undergoes enterohepatic recirculation

Question 43

When is ezetimbe used

Answer 43

When patient has failed all therapy Can be used as mono therapy or in combo with statins

Question 44

Toxicity of ezetimbe

Answer 44

Abdominal pain Diarrhea Cramping Fatigue Back pain When used with statin incidence of myopathy is the same with statin monotherapy

Question 45

Fibrates Effects

Answer 45

Decrease plasma triglycerides Significantly decrease in VLDL levels Increase HDL levels

Question 46

Mechanism of action fibrates

Answer 46

Binds to PPAR a Causes effects on lipoprotein metabolism Activation of PPARs and altered gene expression

Question 47

Fibrates binding toPPARa causes

Answer 47

Fatty and oxidation, lowering VLDL

Question 48

Fibrate stimulation of lipoprotein lipase causes

Answer 48

Removal of TG from plasma VLDL

Question 49

What to all fibrates do

Answer 49

Increase turnover and removal of cholesterol from liver

Question 50

True or false: Fenofibrate and chlorofibrate are prodrugs

Answer 50

True

Question 51

Metabolism of Fibrates

Answer 51

undergo hydrolysis to produce acid form Active metabolite can be further oxidized or conjugated until products are inactive

Question 52

Active fibrates

Answer 52

Gemfibrozil Ciprofibrate Bezafibrate

Question 53

How are active fibrates deactivated

Answer 53

Oxidation and conjugation

Question 54

Fibrate toxicity

Answer 54

Chlorofibrate has many side effects § Higher morbidity and mortality § Malignancy, gallbladder disease, pancreatitis § Like HMGRIs, they can cause myopathy, myositis, rhabdomyolysis § Increased risk of gallstones due to increased excretion of cholesterol in bile § Increases hypoprothrombinemic effect when taken with anticoagulants (low prothrombin)