CV Case Study: Statins Flashcards
What are the functions of cholesterol?
Steroid hormones
Bile acids
Biological membranes
How is steroid hormones a function?
Cholesterol is the precursor for many hormones
eg. sex, tissue growth hormones
How is bile acids a function?
Cholic acid is an emulsifying agent = aids digestion
How is biological membranes a function?
Cholesterol is a structural component
What is cholesterol?
Fatty molecule transported round blood supply by LDLs + HDLs
What do LDLs do?
Carry cholesterol to cells
What do HDLs do?
Carry cholesterol from cells to liver
What can cholesterol cause?
Fatty plaques in arteries leading to risk of atherosclerosis, clot formation, stroke + heart attack
What does cholesterol have?
Hydrophilic head
Hydrophobic tail
What are the 3 main phases of the pathway of the biosynthesis of cholesterol?
Formation of mevalonic acid
Conversion of mevalonate into farnesyl pyrophosphate
Condensation of 2 farnesyl pyrophosphate to yield squalene
Describe what happens in phase 1
Formation of mevalonic acid
Thioester precursor
Thiolase condenses precursor
HMG CoA synthetase
HMG CoA reduced to mevalonic acid
How do statins work?
By blocking HMG-CoA reductase
Statins are competitive inhibitors of this
Describe the catalytic mechanism
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
What is the structure of Type 1 statins?
Polar head
Hydrophobic moiety
What are examples of Type 1 statins?
Lovastatin
Simvastatin
What type of drugs are lovastatin + simvastatin?
Prodrugs where lactone ring is hydrolysed to give polar head
Why are Type 1 difficult to synthesise?
Large number of chiral centres
= hard to get all in correct orientation
What are the side effects of statins?
Constipation
Diarrhoea
Nausea/vomiting
Headache
What type of drugs are Type 2 statins?
Synthetic drugs
What is the structure of Type 2?
Larger hydrophobic moiety
No asymmetric centres
What is an example of Type 2 statin?
Rosuvastatin
What do all statins have in common?
Same mode of binding
= polar head unit
Why do Type 2 have lower side effects?
Less hydrophobic
= do NOT cross cell membranes as easily
What is a common side effect of Type 2?
Muscle pain (myalgia)
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
Why is rosuvastatin a more potent statin?
Forms additional H-bond interactions
How are Atorvastatin, Pitavastatin + Fluvastatin metabolised?
Hydroxylation of aromatic ring
CYP450 stick OH on
How are Lovastatin, Simvastatin + Pravastatin metabolised?
Hydrolysis of lactone or ester
