CV Case Study: Statins

Question 1

What are the functions of cholesterol?

Answer 1

Steroid hormones
Bile acids
Biological membranes

Question 2

How is steroid hormones a function?

Answer 2

Cholesterol is the precursor for many hormones
eg. sex, tissue growth hormones

Question 3

How is bile acids a function?

Answer 3

Cholic acid is an emulsifying agent = aids digestion

Question 4

How is biological membranes a function?

Answer 4

Cholesterol is a structural component

Question 5

What is cholesterol?

Answer 5

Fatty molecule transported round blood supply by LDLs + HDLs

Question 6

What do LDLs do?

Answer 6

Carry cholesterol to cells

Question 7

What do HDLs do?

Answer 7

Carry cholesterol from cells to liver

Question 8

What can cholesterol cause?

Answer 8

Fatty plaques in arteries leading to risk of atherosclerosis, clot formation, stroke + heart attack

Question 9

What does cholesterol have?

Answer 9

Hydrophilic head
Hydrophobic tail

Question 10

What are the 3 main phases of the pathway of the biosynthesis of cholesterol?

Answer 10

Formation of mevalonic acid
Conversion of mevalonate into farnesyl pyrophosphate
Condensation of 2 farnesyl pyrophosphate to yield squalene

Question 11

Describe what happens in phase 1
Formation of mevalonic acid

Answer 11

Thioester precursor
Thiolase condenses precursor
HMG CoA synthetase
HMG CoA reduced to mevalonic acid

Question 12

How do statins work?

Answer 12

By blocking HMG-CoA reductase
Statins are competitive inhibitors of this

Question 13

Describe the catalytic mechanism

Answer 13

Histidine acts as an acid catalyst
Lysine stabilises negatively charged oxygen on Mevaldyl-CoA
Lowers Ea for first step
Glutamic acid acts as an acid catalyst
Astarte residue stabilises Glu + Lys

Question 14

What is the structure of Type 1 statins?

Answer 14

Polar head
Hydrophobic moiety

Question 15

What are examples of Type 1 statins?

Answer 15

Lovastatin
Simvastatin

Question 16

What type of drugs are lovastatin + simvastatin?

Answer 16

Prodrugs where lactone ring is hydrolysed to give polar head

Question 17

Why are Type 1 difficult to synthesise?

Answer 17

Large number of chiral centres
= hard to get all in correct orientation

Question 18

What are the side effects of statins?

Answer 18

Constipation
Diarrhoea
Nausea/vomiting
Headache

Question 19

What type of drugs are Type 2 statins?

Answer 19

Synthetic drugs

Question 20

What is the structure of Type 2?

Answer 20

Larger hydrophobic moiety
No asymmetric centres

Question 21

What is an example of Type 2 statin?

Answer 21

Rosuvastatin

Question 22

What do all statins have in common?

Answer 22

Same mode of binding
= polar head unit

Question 23

Why do Type 2 have lower side effects?

Answer 23

Less hydrophobic
= do NOT cross cell membranes as easily

Question 24

What is a common side effect of Type 2?

Answer 24

Muscle pain (myalgia)

Question 25

Describe the mechanism of action for statins

Answer 25

Competitive inhibitor of HMGR
Polar head mimics natural substrate
Binds more strongly than natural substrate
BUT does NOT undergo reaction = NO LG

Question 26

Why is rosuvastatin a more potent statin?

Answer 26

Forms additional H-bond interactions

Question 27

How are Atorvastatin, Pitavastatin + Fluvastatin metabolised?

Answer 27

Hydroxylation of aromatic ring
CYP450 stick OH on

Question 28

How are Lovastatin, Simvastatin + Pravastatin metabolised?

Answer 28

Hydrolysis of lactone or ester