lipitor

Question 1

characteristics of cholesteol

Answer 1

Found in ALL animal cells
Important constituent of membranes
Provides strength
Helps create proper “liquidity”
Continuously made and recycled in the body
Minimum amounts required for good health
Too much causes problems

Question 2

where does cholesterol come from?

Answer 2

Diet makes a very small contribution
Animal sources
Majority of our cholesterol is made in liver
Saturated fats
Trans fats

Question 3

cholesterol is made in the liver from_____. How many enzymes are involved? What does it begin as?

Answer 3

saturated fats
Acetyl-CoA
23 enzymes
Distributed to all cells in the body via blood

Question 4

synthesis of mevalonic acid. What is it?

Answer 4

Acetyl-CoA–>HMG CoA–> Mevalonic acid by HMG CoA reductase

Raw material to make cholesterol

Question 5

Excess cholesterol stored in______? It is built up inside of _________ as ______?

Answer 5

arterial walls
arterial lining
plaque

Question 6

oxidation of of plaque in cholesterol

Answer 6

cholesterol–>oxidation–>cholestenone (foreign)

Question 7

oxidized cholesterol attracts______? These consume cholesterol becoming______? Inflammation causes plaque to___? _____ forms over the ___ plaque

Answer 7

macrophages
foam cells
burst
blood clot, burst

Question 8

prevent heart attack through diet

Answer 8

Reduce total fat in diet
Average North American eats 3X RDA
Avoid processed foods
Saturated fat
Trans fat
Reduce meat intake
Eat fruits and vegetables
Reduce total food intake

Question 9

triparanol

Answer 9

Effective in lowering blood cholesterol
Caused cataracts
Removed from market 1962
Used as an example in medical textbooks
Physicians afraid of cholesterol lowering drugs

Question 10

which enzyme does triparanol inhibit

Answer 10

the last one

Question 11

triparanol ineffective b/c? what should we do instead?

Answer 11

Buildup of synthetic intermediates can cause toxicity
Block an early enzyme, fewer intermediates build

For safety need to inhibit early in the sequence

Question 12

Mevastatin is a

Answer 12

Competitive inhibitor of HMG CoA reductase and a pro drug as it resembles HMG reductase component in mechanism which causes the molecule to bind to the same place that HMG CoA (3rd enzyme) and causes inhibition

Question 13

Lovostatin HMG reductase inhibitor

Answer 13

no toxicity issues
msuhroom

Question 14

triparanol made doctors afraid to prescribe statins

Answer 14

Effective in lowering blood cholesterol
Caused cataracts
Removed from market
Case study in textbooks

Question 15

drug companies educated doctors

Answer 15

Triparanol was an example in textbooks
Suggested that inhibition of cholesterol biosynthesis might be dangerous
Enzyme targeted was late in the sequence
Buildup of insoluble intermediates

New drugs inhibited a different enzyme
Enzyme target was early in the sequence
Avoids buildup problem

Question 16

to prove doctors: Four-S study of Simvastatin

Answer 16

4,444 patients
35 % reduction in cholesterol
42 % less likely to die of heart attack
Non-heart related deaths at normal rates
Sales of all statin drugs rose

Question 17

statins are complex structures. are synthetic versions possible

Answer 17

merek started single ring system
pfizer continued idea by using linker optimizer
inhibitory concentration for 50% want the smallest IC50 RATIONAL DRUG DESIGN, sAR for picking best f’nal groups

wanted maximum potency (smallest dosage b/c doctors though smaller doses are safer b/c PTSD from triparamol, most active)
used single enantiomer
lipitor is 4th in the market

Question 18

lipitor

Answer 18

Total sales since 1996
$131 Billion
Very effective
Extremely safe
Patent expired 2011
Generics now available

best selling drug in history

Question 19

genetic versions of lipitor

Answer 19

improved biocatalysis