Statins

Question 1

why is cholesterol a key component of the cell membrane?

Answer 1

• fluidity (prevents membranes from becoming too rigid or too permeable)
• stability (helps maintain membrane integrity)

Question 2

what an excess cholesterol lead to?

Answer 2

plaque formation in arteries, increasing the risk of heart attack and stroke

Question 3

what are the main cardiovascular conditions assocaited with high cholesterol and atherosclerosis

Answer 3

• coronary artery disease
• peripheral artery disease
• stroke

Question 4

what is the endogenous cholesterol levels in the body

Answer 4

the liver makes most of the cholesterol via the mevalonate pathway, where HMG-coA reductase is the rate limiting enzyme (~70-80% total cholesterol)

Question 5

what is exogenous cholesterol?

Answer 5

found in animal based foods:
- meat, poultry, fish
- dairy products
- eggs

~20-30% total cholesterol

Question 6

what are additional factors affecting levels of cholesterol?

Answer 6

genetics (LDL receptor defects)
lifestyle
hormones

Question 7

how is cholesterol transported?

Answer 7

via lipoproteins (LDL, HDL, VLDL) because it is insoluble in water

Question 8

what is the function of LDL?

Answer 8

carries cholesterol from the liver to peripheral tissues for membrane synthesis and hormone production

Question 9

what is the problem with LDL?

Answer 9

excess LDL
- cholesterol deposits in artrial walls
- atherosclerotic plaque formation
- increased risk of heart attack and stroke

Question 10

how does saturated trans fats increase LDL

Answer 10

reducing LDL receptor activity
increasing hepatic cholesterol synthesis

Question 11

what is the function of HDL?

Answer 11

performs reverse cholesterol transport - removes excess cholesterol from tissues and arteries, returing it to the liver for excretion

protective role: higher LDL levels are associated with lower CV risk

Question 12

what happens when hepatocyte intracellular cholesterol is low?

Answer 12

• sterol regulatory element binding protein is released into the cytoplasm of hepatocytes
• SREBP moves to the nucleus to upregulate HMGCR expression via enhanced gene expression
• increased HMGCR leads to increased cholesterol synthesis in hepatocytes
• cholesterol is exported form the liver packaged with LDL

Question 13

what are the mechanisms of the HMG coA reductase pathway?

Answer 13

1. feeback inhibition by cholesterol and its derivatives
2. hormonal regulation
3. transcriptional control via SREBP

Question 14

how do statins target LDL?

Answer 14

• by inhibiting HMG-coA reductase, statins reduce hepatic cholesterol synthesis
• this triggers upregulation of LDL receptors on hepatocytes - more LDL cleared from blood
• results: significant LDL-cholesterol reduction (20-60%)

Question 15

what statins are pro drugs?

Answer 15

simvastatin and lovastatin (ring is closed)

Question 16

what does HMG CoA reducatase catalyse the reduction of

Answer 16

HMG-COA to mevalonate using the cofactor NADPH

Question 17

what are diadvantages of type 1 statins?

Answer 17

1. difficulty to synthesise and manufacture because of large number of chiral centres
2. specific adverse effect profile associated with muscle pain and longer term myopathy and more rarely can lead to rhabdomyolysis

Question 18

what was the first type 2 statin and how was the structure different

Answer 18

atovastatin - repplacing the chiral lipophillic moiety that binds hydrophobic pockets as an easily accessible lipophillic moiety without chiral centres

Question 19

what statins are associated with muscle related side effects and why?

Answer 19

lovastatin, simvastatin, atorvastatin and fluvastatin - they all have a high log P so can passively diffuse into skeletal muscle, increasing the risk of toxicity

Question 20

how can statins cause mitochondrial dysfunction?

Answer 20

by inhibitng HMG coA reductase they also reduce movalonate pathway intemediates such as co enzyme Q10 which is essential for mitochondrial electron transport and ATP production in muscle, this can impair energy metabolism leading to muscle pain, weakness and fatigue

Question 21

what are hydrophillic statins and how do they work?

Answer 21

eg. rosuvastatin, pravastatin
- polar and have low lipid solubility
- cannot easily cross cell membranes by passive diffusion, so dont widely distribute into extrahepatic tissues (like muscle and Brain)

Question 22

how is hydrophilic statins taken up into the liver?

Answer 22

by OATP transporters on hepatoctyes (minimal penetration to non-hepatic tissues so reduces side effects)

Question 23

what does hydrophillic statins have ?

Answer 23

• polar functional groups
• negative charge at physiological pH
• these features bind the OATP bidning pocket, which favours ionic and hydrogen bonding interactions rather than hydrophobic