CV Case Study: Statins Flashcards

1
Q

What are the functions of cholesterol?

A

Steroid hormones
Bile acids
Biological membranes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

How is steroid hormones a function?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How is bile acids a function?

A

Cholic acid is an emulsifying agent = aids digestion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

How is biological membranes a function?

A

Cholesterol is a structural component

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is cholesterol?

A

Fatty molecule transported round blood supply by LDLs + HDLs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What do LDLs do?

A

Carry cholesterol to cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What do HDLs do?

A

Carry cholesterol from cells to liver

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What can cholesterol cause?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What does cholesterol have?

A

Hydrophilic head
Hydrophobic tail

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Describe what happens in phase 1
Formation of mevalonic acid

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How do statins work?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Describe the catalytic mechanism

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the structure of Type 1 statins?

A

Polar head
Hydrophobic moiety

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are examples of Type 1 statins?

A

Lovastatin
Simvastatin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What type of drugs are lovastatin + simvastatin?

A

Prodrugs where lactone ring is hydrolysed to give polar head

17
Q

Why are Type 1 difficult to synthesise?

A

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

18
Q

What are the side effects of statins?

A

Constipation
Diarrhoea
Nausea/vomiting
Headache

19
Q

What type of drugs are Type 2 statins?

A

Synthetic drugs

20
Q

What is the structure of Type 2?

A

Larger hydrophobic moiety
No asymmetric centres

21
Q

What is an example of Type 2 statin?

A

Rosuvastatin

22
Q

What do all statins have in common?

A

Same mode of binding
= polar head unit

23
Q

Why do Type 2 have lower side effects?

A

Less hydrophobic
= do NOT cross cell membranes as easily

24
Q

What is a common side effect of Type 2?

A

Muscle pain (myalgia)

25
Describe the mechanism of action for statins
Competitive inhibitor of HMGR Polar head mimics natural substrate Binds more strongly than natural substrate BUT does NOT undergo reaction = NO LG
26
Why is rosuvastatin a more potent statin?
Forms additional H-bond interactions
27
How are Atorvastatin, Pitavastatin + Fluvastatin metabolised?
Hydroxylation of aromatic ring CYP450 stick OH on
28
How are Lovastatin, Simvastatin + Pravastatin metabolised?
Hydrolysis of lactone or ester