Antilipidemics (2) Flashcards
T/F cholesterol levels and statins are still controversial with suggestions that lower the better
true
Even at levels within normal range, statins may cause ______
endothelial dysfunction
Four groups targeted for statins
- people who already have heart disease
- LDL levels >190
- T2D between 40-75
- People 40-75 who have estimated 10 year risk of heart attack or stroke of 7.5 or higher
What % of men are recommended to take statins?
44%
What % of women of women are recommended to take statins
15%
What is another name for the HMG-CoA reductase pathway?
mevolonate pathway
Statins inhibit what?
HMG-CoA reductase
What animal model is indicated to be the best?
dog especially when pretreated with cholestyramine
What was the first statin created, but never made it to the market?
Mevastatin
Lovastatin metabolism
by CYP3A4 no grapefruit juice
which statin is cleared by the kidneys?
pravastatin
Fluvastatin metabolism
multiple CYP enzymes envolved in metabolism (2C9, 3A4, 2C)
T/f generally the more CYPs metabolized the less DDI
true
T/F fluvastatin has more DDI than other statins
false
what is the world’s best selling medication?
atorvastatin
Why was cerivastatin voluntarily withdrawn from the market?
fatal rhabdomyolysis
what is considered a super statin?
rosuvastatin
Which statin has a FDA advisory for east asian patients and why?
rosuvastatin risk of myopathy due to how the drug is processed
Pitavastatin metabolism
glucurondiation CYP450 (NOT 3A4)
Which statin has neutral effect on glucose regulation?
pitavastatin
Which statin appears to have improved tolerability in its metabolic profile?
pitavastatin
All statin mimic what?
HMG-CoA (S) 3-hydroxy-3-methylgluteryl CoA
statins are what kind of inhibitors with human enzyme
co-crystallized
T/f due to statins flexibility, they bind not only to HMG-binding pocket but also part of the CoA binding surface
true
T/F not all statins bind to the same binding pocket
false! All fill same pocket
The 6 fluoro ring of statins stacks between what?
Arg590 and phenyl ring
The 6 fluoro ring of statins has polar interaction between what?
N of Arg590 and fluorine
the sulfonamide of rosuvastatin has polar interaction with____
Arg568
the polar side chain of atorvastatin what interactions?
H bond with Ser565
The _____ ring system is necessary to anchor statins to active site (SAR)
decalin **replacing with cyclohexane ring reduces activity 10,000 fold
(SAR) t/f replacing ester with ether increases activity of statins
false!! decreases activity
(SAR) t/f stereochemistry on ester side chain of statins is important
false! not important
(SAR) ____ substitution (R2) increases activity
methyl
(SAR) Introduction of ____ increases hydrophilicity and may enhance cellular _____
B-OH (above plane R1) specificity
(SAR) W,X,Y can either be ____ or _____ and ___ or ____ membered ring
C or N
5 or 6
(SAR) t/f p-fluorine cannot be coplanar with central aromatic ring
true!
decreases activity
(SAR) substiution of ____ groups enhances lipophilicity and inhibitor activity
aryl
T/F cats are more sensitive to statins
False
Dogs!
Statins metabolism
extensive 1st pass
excreted in bile
*lactone must be hydrolyzed for activity
**species differences
What are the 3 ways statins can be metabolized?
- 6 B-hydroxy
- 3 hydroxy
- 6 exomethylene
How is atorvastatin metabolized?
Active or inactive?
o,p hydroxylation
active
How is fluvastatin metabolized?
Active or less active?
hydroxylation
active
How is cervastatin metabolised?
Active or less active?
demethylation
less active
T/F you can use statins with bile acid sequestrants and niacin
True, but not multiple statins at the sasme time
T/F statins are not used in pregnant or lactating women
true
statins use
hypercholesteremia
familial hyperlipidemia
ADE statins
most directly related to their biochemical MOA and are result of potent and reversible inhibition of an enzyme involved in homeostasis
toxicity studies show targets of statins are
liver
kidney
muscle
nonglandular stomach
lymph
eyes, CNS, testes
Type I vs Type II statin
Type I: declain ring
Type II: fluorophenyl group
What is the enzyme?
HMG CoA reductase
How did lovastatin differ from mevastatin?
Lovastatin: CH3
Mevastatin: H
What are most statins CI?
pregnancy
breastfeeding
liver diseaee
