Atherosclerosis Flashcards
Describe the exogenous cholesterol transport pathway
- Dietary fat is broken down in the GIT into cholesterol, fatty acids and mono- and diglycerides
- These molecules form water-soluble micelles with bile acids
- In the duodenum almost all the TG is absorbed
- Chylomicron formation
- chylomicron enters the blood via lymphatics and thoracic duct
- Passes various endothelial tissues that contain lipoprotein lipase,
- Break down TGs intoFAs which are absorbed into fat and muscle
- The chylomicron remnants with cholesterol are taken up by the liver by remnant receptors
Describe the endogenous cholesterol transport pathway
- The liver produces cholesterol from acetyl CoA and takes up excess TGs and cholesterol from the diet
- During fasting the cholesterol is released with TGs and VLDLs
- Lipoprotein lipase releases the TGs from the VLDLs to form IDLs
- Further release of TGs forms LDLs (rich in cholesterol)
- The LDLs deliver cholesterol to cells/endocytosed into liver cells by binding to LDL receptors
What is cholesterol ester transfer protein involved in
CETP, involved in forming small dense LDLs
CETP transfers TGs from VLDLs/chylomicrons/HDLs to LDL
Lipases releases these TGs from the LDL to leave a small and dense LDL
Describe the reverse cholesterol transport pathway
Cholesterol in cells can be removed by HDLs
HDLs takes up cholesterol from cells and uses CETP to take up TGs from VLDLs
HDLs release the cholesterol at the liver, which is then taken up by scavenger receptors for future use or excretion by the liver
Describe how macrophages are recruited in atherosclerosis formation
- Excess LDLs and small dense LDLs can get into the sub endothelial layer of an artery (tunica intima)
- The prone areas where this occurs are highly odixative
- LDLs oxidised by free radicals
- Endothelial cells detect this and recruit monocytes
- Movement into the intimate
- Monocytes become macrophages in tissue
- Scavenger receptor used to phagocytose the oxidise LDLs to form foam cells
- Stimulates chronic inflammation
- Cycle of lipoprotein oxidisation, macrophage recruitment and phagocytosis
Explain how macrophages cause atheroma development
- Macrophages stimulate proliferation of smooth muscle cells and increased collagen synthesis
- This forms a fibrous cap around the mass of foam cells (fatty streak)
- The mass can rupture through the cap and endothelium, leading to thrombosis
Why is there a increased risk of cardiovascular disease in atherosclerosis
Chylomicron remnants, IDLs, LDLs and small dense LDLs are highly atherogenic
Saturated fats increase the amount of these lipoproteins, increasing risk of cardiovascular disease
What class of drug are statins and give some examples
HMG-CoA reductase inhibitors
Atorvastatin, simvastatin and pravastatin
Describe the pharmacokinetics of statins
Mainly metabolised by CYP34 except pravastatin which isn’t metabolised
What does doubling the dose of a statin cause
Causes a 6% reduction in LDLs
Describe the pharmacodynamics of statins
Inhibits HMG-CoA reductase, blocking cholesterol synthesis in the liver
This leads to more LDL receptors being expressed on the liver and so more LDLs are take up into the liver
Give the reaction that statins inhibit
2 x acetyl coA -> acetoacetyl-CoA -> 2-hydroxy-3-methylglutaryl CoA -> Mevalonic acid
HMG-CoA reductase catalyses the last step
What class of drug is gemifibrozil and describe its pharmacodynamics
Fibrates
Activates peroxisome proliferation activated alpha (PPAR-a) receptors
This leads to a reduction in plasma fatty acids and TGs
What class of drug is Ezetimibe and describe its pharmacodynamics
Cholesterol absorption inhibitor
It inhibits cholesterol absorption in the small intestine and so reduces LDL cholesterol by a reasonable amount
Often given with statins
What class of drug is Torcetrapib and what are its side effects
Cholesterol ester transfer protein inhibitor
activation of aldosterone synthase leading to raised BP (not used anymore)
