08-02-22 - Cholesterol Lowering Drugs Flashcards
Learning outcomes
- To describe the sources of cholesterol in the blood and how it is transported
- To recognise the association of high blood cholesterol levels with atherosclerosis
- To list the drugs used to lower blood cholesterol levels
- To explain the mechanisms of action of these drugs
- To relate the mechanisms of action of these drugs to the therapeutic outcome
- To identify the major side effects of these drugs
Describe the structure of lipoproteins
• Lipoproteins consist of a central core of hydrophobic lipids, which are either triglycerides or cholesterol esters
• Hydrophilic coat of polar substances:
1) Phospholipids
2) Free cholesterol
3) Associated proteins (apoproteins or apolipoproteins)
What are the 5 main classes of lipoproteins?
What 4 things do these classes differ by?
• 5 main classes of lipoproteins:
1) High density lipoproteins (HDL)
2) Intermediate density lipoproteins (IDL)
3) Low density lipoproteins (LDL)
4) Very low-density lipoproteins (VLDL)
5) Chylomicrons
• These classes differ by:
1) Core lipids
2) Apoproteins
3) Size
4) Density
What are the 2 cholesterol pathways in the body?
What is the role of the liver in these pathways?
- Exogenous cholesterol pathway – source of cholesterol from the diet
- Endogenous pathway – cholesterol made in the body by cells
- The liver is the centre of these pathways, and can sense and monitor its stores of cholesterol and judge what it does based on this to keep cholesterol levels in check
Describe the steps 5 in the role of chylomicrons in the exogenous pathway.
Describe the steps in the role of VLDL in the Endogenous pathway
• role of chylomicrons in the exogenous pathway:
1) Chylomicrons transport triglycerides and cholesterol from the GI to the tissues
2) Chylomicrons are then split by lipoprotein lipase to release free fatty acids (FFAs)
3) FFAs taken up by muscle and adipose tissue
4) Chylomicron remnants taken up in the liver
5) The cholesterol is stored, oxidised to bile acids or released to VLDL
• Steps in the role of VLDL in the Endogenous pathway:
1) VLDL transports cholesterol and newly synthesised TG to tissues
2) TGs removed from VLDL leaving LDL with a high cholesterol concentration, which is taken up by cells or the liver
3) HDL absorbs cholesterol from cell breakdown and transfer it to VLDL and LDL
What is hyperlipidaemia?
What is it associated with?
What 4 things might this lead to?
What is an increased risk of atherosclerosis and CHD associated with?
- Hyperlipidaemia is an increase in the plasma concentration of lipids
- Hyperlipidaemia is associated with an increase in LDL, which is a risk factor for atheromatous disease
• This may lead to:
1) Atherosclerosis
2) Ischaemic heart disease
3) Myocardial infarction
4) Cerebral vascular accidents
• An increase in risk of atherosclerosis and CHD associated with a high plasma concentration of total and LDL cholesterol
What are the 4 different levels of cholesterol concentration?
What 2 things need to be taken into account when talking about cholesterol level?
• 4 different levels of cholesterol concentration:
1) Ideal level – (<5mmol/l)
2) Mildly high cholesterol level (5 to 6.4mmol/l)
3) Moderately high cholesterol level (6.5 to 7.8 mmol/l)
4) Very high cholesterol level (>7.8mmol/l)
• Also need to take into account:
1) The ratio between the ‘good’ HDL and ‘bad’ LDL cholesterol
2) Other risk factors for CV disease e.g smoking, diabetes, high blood pressure
What are the 2 ways lipid lowering drugs work?
What is the aim of these drugs?
What should be considered before drugs?
What are the 3 sources cholesterol is derived from?
• Lipid lowering drugs work by either:
1) Reducing production of lipoproteins
2) Increasing their removal from the blood
- The aim is to reduce plasma cholesterol
- Lifestyle modification (e.g diet and exercise) is the first step, drug therapy should be secondary
• Cholesterol is derived from:
1) De novo synthesis in the liver
2) Uptake from circulating LDLs
3) Uptake of chylomicron remnants
What are the 4 different actions of cholesterol drugs?
• 4 different actions of cholesterol drugs:
1) Sequester bike acids in the intestine/decrease stores of cholesterol
• Colestyramine
2) Inhibit transport protein for cholesterol in the brush border of enterocytes in the duodenum
• Ezetimibe
3) Alter the levels of plasma lipoproteins • Fenofibrate • Bezafibrate • Gemfibrozil • Nicotinic acid
4) Inhibit synthesis of cholesterol in the liver • Simvastatin • Pravastatin • Atorvastatin • Rosuvastatin
What is colestyramine?
What actions does this lead to?
How can you lower blood cholesterol by 50%?
- Colestyramine is a basic anion exchange resin
- Colestyramine:
1) Sequesters (isolate/hide away) bile acids to prevent enterohepatic recirculation, which increases the metabolism of endogenous cholesterol into bile acids
2) Increases LDL receptor numbers in the liver, resulting in the removal of LDLs from the blood
• Bile-sequestering drugs plus inhibitors of cholesterol biosynthesis can lower blood cholesterol by 50%
What is the action of fibrates?
What are 2 examples of fibrates?
What are the 5 actions of these 2 drugs?
• Fibrates are activators of lipoprotein lipase
• 2 examples of fibrates:
1) Fenofibrate
2) Gemfibrozil
• 5 actions of fenofibrate and gemfibrozil:
1) Decreases triglycerides and cholesterol
2) Particularly decreases concentrations of VLDL
3) Main action is stimulation of lipoprotein lipase which decreases the triglyceride content of VLDL
4) Clearance of LDL by the liver is also stimulated
5) Increases HDL production and reverse cholesterol transport
What are 3 clinical uses of fibrates?
• Clinical uses of fibrates:
1) Mixed dyslipidaemia (raised serum triglyceride as well as cholesterol
2) Used in patients with low HDL and high risk of atheromatous disease (e.g type 2 diabetes)
3) Combined with other lipid-lowering drugs in patients with severe treatment resistant dyslipidaemia
What is nicotinic acid?
What are the 2 actions of nicotinic acid?
What is the action of ezetimibe?
How does it do this?
- Nicotinic acid (niacin) is an example of a vitamin with lipid-lowering properties
- 2 actions of nicotinic acid:
1) Lowers VLDL production, which leads to a decrease in LDL
2) Activates lipoprotein lipase
- Ezetimibe specifically reduces intestinal cholesterol absorption
- It does this by inhibiting a sterol carrier protein the brush border of enterocytes
What are statins?
What are they used for?
What are the 2 actions of HMG-CoA reductase?
What are 4 examples of statins?
What is their action?
What are the 2 halves of the mevalonate pathway?
What is protein prenylation?
What does it ensure?
- Statins are HMG-CoA reductase inhibitors
- Statins are they key drugs used in the management of hyperlipidaemia
• Action of HMG-CoA reductase:
1) Major rate-limiting step in cholesterol synthesis
2) Converts HMG-CoA to mevalonic acid (MVA)
• 4 examples of statins:
1) Simvastatin
2) Pravastatin
3) Atorvastatin
4) Rosuvastatin
- All of these statins are long-lasting HMG CoA reductase inhibitors
- One half of the mevalonate pathway is cholesterol synthesis, while the other half is protein prenylation
- Protein prenylation is the addition of lipid tails to small GTPase signalling molecules
- This ensures they are localised correctly
What are 3 clinical uses of statins?
• Clinical uses of statins:
1) Secondary prevention of myocardial infarction and stroke in those who have atherosclerotic disease
2) Primary prevention of arterial disease in patients with high serum cholesterol
3) Atorvastatin lowers serum cholesterol in familial hypercholesterolaemia
