Cholesterol lowering drugs Flashcards
Describe the structure of a lipoprotein
- Central core of hydrophobic lipid (Triglyceride or cholesterol esters)
- Hydrophilic coat of polar substances (Phospholipids, free cholesterol and associated proteins; apoproteins or apolipidproteins)
What are the 5 classes of lipoproteins?
1) High density lipoprotein (HDL)
2) Intermediate density lipoprotein (IDL)
3) Low density lipoprotein (LDL)
4) Very low density lipoprotein (VLDL)
5) Chylomicrons
Rank from smallest to largest, the classes of lipoprteins
- High density lipoprotein
- Low density lipoprotein
- Intermediate lipoprotein
- Very low density lipoprotein
- Chylomicron Remnant
What varies between the different classes of lipoprotein?
- Core lipids (Ratio of triglycerides to cholesterol)
- Size
- Density
- Apoproteins
What is the role of lipoprotein?
Transport hydrophobic substances e.g. cholesterol
What are the two ways that the body can get cholesterol?
1) Exogenous pathway: Cholesterol is taken in from the diet and absorbed in the gut
2) Endogenous pathway: Cholesterol is produced in the liver
Describe the exogenous pathway for cholesterol
- Dietary cholesterol is taken in
- broken down into fatty acids, glycerol and cholesterol
- Products are absorbed (some of these require active processes)
- Fatty acids and cholesterol are taken up into Chylomicrons (rich triglyceride centre > CE)
- Enters into circulation
- Interact with specific tissues (vascular endothelium of peripheral tissues) and bind to lipoprotienlipases, which generate free fatty acids from the centre
- This reduces the triglyceride content form the centre of the chylomicrons forming chylomicron remnants (CE>TG) which are circulated to the liver
- Interaction with surface receptors causes endocytosis and the distribution of the CE rich core
- Some cholesterol can be requested with bile acid
- Can strip excess cholesterol out into the GI system if there is too much
Describe the endogenous pathway
- There is a source of Acetyl-coenzyme A which can be used to form Cholesterol (process)
- The cholesterol level is regulated by the amount of free cholesterol in the diet
- The cholesterol is packaged into VLDL (high content of triglycerides>CE)
- These can be recognised by lipoproteinases which causes the release of fatty acid into tissues
- This causes the formation of LDLs (CE) which delivers the cholesterol to the tissues requiring it
- These are then taken back to the liver where they are endocytosed
What happens to cholesterol released by dying cells?
- Taken up by high density lipoprotein
* HDL is repackaged to LDLs or VLDLs
What is the role of Chylomicrons?
- Transports Triglycerides and cholesterol esters from the GI system to tissue
- Split by lipoprotein lipase to release free fatty acids which are taken up by muscle and adipose tissue
What is the role of Chylomicron remnants?
- Taken up by the liver
* Cholesterol is then stored, oxidised to bile acids or released to VLDL
What is the role of VLDL?
- Transports cholesterol and newly synthesised Triglycerides to tissues
- Triglycerides are removed from VLDL leaving LDL with a high cholesterol
What is the role of HDL?
• Absorbs cholesterol from cell breakdown and transfers it to VLDL and LDL
What is high plasma cholesterol associated with high LDL a risk factor for?
• Coronary heart disease • Atheromatous disease • May lead to: - Atherosclerosis - Ischaemic heart disease - Myocardial infarction - Cerebral vascular accidents
What is hyperlipidaemia?
An increase in the plasma concentration of lipids
What is the average total cholesterol level in the UK?
5.7mmol/l
What is the ideal level of cholesterol?
<5mmol/l
What is a moderately high cholesterol level?
6.5 to 7.8mmol/l
What is a very high cholesterol level?
> 7.8mmol/l
When looking at a person’s cholesterol level, what must also be taken into account?
- Ratio between ‘good’ HDL and ‘bad’ LDL cholesterol
* Other risk factors for cardiovascular disease
Which 3 sources is cholesterol derived from?
- De novo synthesis in the liver
- Uptake from circulating LDLs
- Uptake of chylomicron remnants
Give the 4 mechanisms used by lipid lowering drugs
- Sequester bile acids in the intestine/ decrease hepatic stores of cholesterol
- Inhibit transport protein for cholesterol on the brush border of enterocytes in the duodenum
- Alter the levels of plasma lipoproteins
- Inhibit the synthesis of cholesterol in the liver
What is Colestramine and how does it work?
- Basic anion exchange resin
- Sequesters bile acids to prevent enterohepatic recirculation
- Increases the metabolism of endogenous cholesterol into bile acids
- Increases LDL receptor numbers in the liver resting in the removal of LDLs from the blood
What can be used to decrease blood cholesterol by 50%?
Bile sequestering drugs and inhibitors of cholesterol biosynthesis
