Antilipidemics (2)

Question 1

T/F cholesterol levels and statins are still controversial with suggestions that lower the better

Answer 1

true

Question 2

Even at levels within normal range, statins may cause ______

Answer 2

endothelial dysfunction

Question 3

Four groups targeted for statins

Answer 3

1. people who already have heart disease
2. LDL levels >190
3. T2D between 40-75
4. People 40-75 who have estimated 10 year risk of heart attack or stroke of 7.5 or higher

Question 4

What % of men are recommended to take statins?

Answer 4

44%

Question 5

What % of women of women are recommended to take statins

Answer 5

15%

Question 6

What is another name for the HMG-CoA reductase pathway?

Answer 6

mevolonate pathway

Question 7

Statins inhibit what?

Answer 7

HMG-CoA reductase

Question 8

What animal model is indicated to be the best?

Answer 8

dog especially when pretreated with cholestyramine

Question 9

What was the first statin created, but never made it to the market?

Answer 9

Mevastatin

Question 10

Lovastatin metabolism

Answer 10

by CYP3A4 no grapefruit juice

Question 11

which statin is cleared by the kidneys?

Answer 11

pravastatin

Question 12

Fluvastatin metabolism

Answer 12

multiple CYP enzymes envolved in metabolism (2C9, 3A4, 2C)

Question 13

T/f generally the more CYPs metabolized the less DDI

Answer 13

true

Question 14

T/F fluvastatin has more DDI than other statins

Answer 14

false

Question 15

what is the world’s best selling medication?

Answer 15

atorvastatin

Question 16

Why was cerivastatin voluntarily withdrawn from the market?

Answer 16

fatal rhabdomyolysis

Question 17

what is considered a super statin?

Answer 17

rosuvastatin

Question 18

Which statin has a FDA advisory for east asian patients and why?

Answer 18

rosuvastatin risk of myopathy due to how the drug is processed

Question 19

Pitavastatin metabolism

Answer 19

glucurondiation CYP450 (NOT 3A4)

Question 20

Which statin has neutral effect on glucose regulation?

Answer 20

pitavastatin

Question 21

Which statin appears to have improved tolerability in its metabolic profile?

Answer 21

pitavastatin

Question 22

All statin mimic what?

Answer 22

HMG-CoA (S) 3-hydroxy-3-methylgluteryl CoA

Question 23

statins are what kind of inhibitors with human enzyme

Answer 23

co-crystallized

Question 24

T/f due to statins flexibility, they bind not only to HMG-binding pocket but also part of the CoA binding surface

Answer 24

true

Question 25

T/F not all statins bind to the same binding pocket

Answer 25

false! All fill same pocket

Question 26

The 6 fluoro ring of statins stacks between what?

Answer 26

Arg590 and phenyl ring

Question 27

The 6 fluoro ring of statins has polar interaction between what?

Answer 27

N of Arg590 and fluorine

Question 28

the sulfonamide of rosuvastatin has polar interaction with\_\_\_\_

Answer 28

Arg568

Question 29

the polar side chain of atorvastatin what interactions?

Answer 29

H bond with Ser565

Question 30

The _____ ring system is necessary to anchor statins to active site (SAR)

Answer 30

decalin \*\*replacing with cyclohexane ring reduces activity 10,000 fold

Question 31

(SAR) t/f replacing ester with ether increases activity of statins

Answer 31

false!! decreases activity

Question 32

(SAR) t/f stereochemistry on ester side chain of statins is important

Answer 32

false! not important

Question 33

(SAR) ____ substitution (R2) increases activity

Answer 33

methyl

Question 34

(SAR) Introduction of ____ increases hydrophilicity and may enhance cellular \_\_\_\_\_

Answer 34

B-OH (above plane R1) specificity

Question 35

(SAR) W,X,Y can either be ____ or _____ and ___ or ____ membered ring

Answer 35

C or N 5 or 6

Question 36

(SAR) t/f p-fluorine cannot be coplanar with central aromatic ring

Answer 36

true! decreases activity

Question 37

(SAR) substiution of ____ groups enhances lipophilicity and inhibitor activity

Answer 37

aryl

Question 38

T/F cats are more sensitive to statins

Answer 38

False Dogs!

Question 39

Statins metabolism

Answer 39

extensive 1st pass excreted in bile \*lactone must be hydrolyzed for activity \*\*species differences

Question 40

What are the 3 ways statins can be metabolized?

Answer 40

1. 6 B-hydroxy 2. 3 hydroxy 3. 6 exomethylene

Question 41

How is atorvastatin metabolized? Active or inactive?

Answer 41

o,p hydroxylation active

Question 42

How is fluvastatin metabolized? Active or less active?

Answer 42

hydroxylation active

Question 43

How is cervastatin metabolised? Active or less active?

Answer 43

demethylation less active

Question 44

T/F you can use statins with bile acid sequestrants and niacin

Answer 44

True, but not multiple statins at the sasme time

Question 45

T/F statins are not used in pregnant or lactating women

Answer 45

true

Question 46

statins use

Answer 46

hypercholesteremia familial hyperlipidemia

Question 47

ADE statins

Answer 47

most directly related to their biochemical MOA and are result of potent and reversible inhibition of an enzyme involved in homeostasis

Question 48

toxicity studies show targets of statins are

Answer 48

liver kidney muscle nonglandular stomach lymph eyes, CNS, testes

Question 49

Type I vs Type II statin

Answer 49

Type I: declain ring Type II: fluorophenyl group

Question 50

What is the enzyme?

Answer 50

HMG CoA reductase

Question 51

How did lovastatin differ from mevastatin?

Answer 51

Lovastatin: CH3 Mevastatin: H

Question 52

What are most statins CI?

Answer 52

pregnancy breastfeeding liver diseaee