Cholesterol Lowering drugs Flashcards
Describe Lipoproteins
- Central core of hydrophobic lipid
- Triglycerides or cholesterol esters
- Hydrophilic coat of polar substances
- Phospholipids
- Free cholesterol
- Associated proteins
- Apoproteins or apoplipoproteins
What do the lipoprotein classes vary in?
- Core lipid
- Apoproteins
- size
- density
What are the classes of lipoproteins?
- High density lipoproteins (HDL)
- Intermediate density lipoproteins (IDL)
- Low density lipoproteins (LDL)
- Very low density lipoproteins (VLDL)
- Chylomicrons
Describe the transportation of cholesterol
- Chylomicrons transport triglycerides and cholesterol esters from the GI to tissues
- Split by lipoprotein lipase to release free fatty acids (FFA)s
- FFAs taken up by muscle and adipose tissue
- Chylomicron remnants taken up in the liver
- Cholesterol stored, oxidised to bile acids or released to VLDL
- VLDL transport cholesterol and newly synthesised triglycerides to tissues
- TGs removed from VLDL leaving LDL with a high cholesterol (taken up by cells or liver)
- HDL absorbs cholesterol from cell breakdown and transfer it to VLDL
Describe lipoprotein metabolism
- Increased plasma cholesterol associated with increase in LDL is a risk factor for atheromatous disease
- may lead to atherosclerosis, ischaemic heart disease, myocardial infarction and cerebral vascular accidents
- An increase in the plasma concentration of lipids is called hyperlipidaemia
- Increased risk of atherosclerosis and CHD associated with high plasma concentration of total and LDL cholesterol
What is high cholesterol?
- he average total cholestesterol level in the UK is 5.7 mmol/l
- Ideal level ( < 5mmol/l)
- Mildly high cholesterol level ( 5 to 6.4 mmol/l)
- Moderately high cholesterol level (6.5 to 7.8 mmol/l)
- Very high cholesterol level (> 7.8mmol/l)
- Also have to take into account
- smoking diabetes and hbp
- ratio between good and bad cholesterol
How do lipid lowering drugs work?
Either by reducing production of lipoproteins or by increasing their removal from the blood
Their aim is to reduce plasma control:
- Lifestyle modification is primary
- Drug therapy is secondary
Where is cholesterol derived from?
- De novo synthesis in liver
- Uptake form circulating LDLs
- Uptake of chylomicron remnants
What is the mechanism of action of bile acid sequestrants?
Sequester bile acids in the intestine/Decrease hepatic stores of cholesterol
What is the mechanism of action of PCSK9 inhibitors?
Enhance the removal of LDL
What is the mechanism of action of ezetimibe?
Inhibit transport protein for cholesterol in the brush border of enterocytes in the duodenum
What is the mechanism of action of fibrates?
Alter the levels of plasma lipoproteins
What is mechanism of action of statins and bempedoic acid
Inhibit the synthesis of cholesterol in the liver
Describe Statins
Mechanism of Action: Statins inhibit HMG-CoA reductase, the enzyme responsible for the rate-limiting step in cholesterol synthesis (conversion of HMG-CoA to mevalonic acid).
Examples of Statins: Atorvastatin, simvastatin, pravastatin, and rosuvastatin are long-lasting HMG-CoA reductase inhibitors.
Clinical Use: Statins are primarily used to reduce LDL cholesterol and lower the risk of cardiovascular diseases like heart attacks and strokes.
Describe mevalonate pathway
One half = Cholesterol synthesis
Other half = protein prenylation - addition of lipid tails to small GTPase signaling molecules which ensures they are localised correctly
What are the clinical uses of statins?
Secondary prevention of myocardial infarction and stroke in those who have atherosclerotic diseases
Primary prevention of arterial disease in patients with high serum cholesterol - prevent the risk of the disease occurring
Atorvastatin lowers serum cholesterol in familial hypercholesterolaemia
How can ezetimibe be used if statins don’t work?
Specifically reduces intestinal cholesterol absorption by inhibiting a sterol carrier protein in the brush border of the enterocytes
How can Bempedoic acid be used if statins don’t work?
Reduces cholesterol synthesis in the liver by inhibiting ATP citrate lyase ( converts citrate to acetyl-CoA
How can PCSK9 inhibitors be used if statins don’t work?
PCSK9 mediates the degradation of LDL receptors on surface of liver cells, inhibiting this enzyme increases the amount of LDL bound and removed by the liver.
How can Alirocumab and Evolocumab be used if statins don’t work?
Monoclonal antibodies that block PCSK9, preventing it from marking LDL-receptors for destruction.
How can inclisiran be used if statins don’t work?
Small interfering RNA which limits PCSK9 production
Identify the major side effects of statins
Myositis, angio-oedema, GI disturbances, insomnia, rash. Strictly contra-indicated in pregnancy.
Identify the major side effects of Bempedoic acid
Anaemia, gout, hyperuricaemia.
Identify the major side effects of PCSK9 inhibitors
Flu like symptoms and muscle pain
Identify the major side-effects of Fibrates
Myositis (esp. in patients with renal impairment), GI disturbances.
Identify the major side effects Colestyramine, ezetimibe
GI symptoms (nausea, abdominal bloating, constipation, diarrhoea).
Describe Fenofibrate & gemfibrozol
- ↓plasma triglycerides and, to a lesser extent, cholesterol
- Particularly ↓ elevated concentrations of VLDL
- Main action is stimulation of lipoprotein lipase which ↓ the triglyceride content of VLDL
- Clearance of LDL by the liver is also stimulated
- ↑ HDL production and reverse cholesterol transport
What are the clinical uses of fibrates?
- In patients with diabetes and mixed dyslipidaemia and and elevated LDL cholesterol.
- In patients with high cardiovascular risk, marked hypertriglyceridaemia and low HDL cholesterol
Describe colestyramine
Is a basic anion exchange resin
- sequesters bile acids to prevent enterohepatic recirculation
- therefore ↑ the metabolism of endogenous cholesterol into bile acids
- ↑ 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%
