Cholesterol Lowering Drugs Flashcards
What forms the central core of a hydrophobic lipid?
Lipoproteins
Provide an example of a hydrophobic lipid in which lipoproteins form a core
– triglycerides or cholesterol esters
What role do lipoproteins play in polar substances?
Hydrophilic coat of polar substances
– phospholipids
– free cholesterol
– associated proteins
• apoproteins or apolipoproteinsWhat features are used to classify lipoproteins?
– core lipids
– apoproteins
– size
– density
What are the five 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
What do chylomicrons do?
Chylomicrons transport TG (triglycerides) and cholesterol esters from the GI to tissues
– Split by lipoprotein lipase to release free fatty acids (FFAs)
– FFAs taken up by muscle and adipose tissue
What happens to chylomicron remnants?
Chylomicron remnants taken up in the liver
– Cholesterol stored, oxidised to bile acids or released to VLDL
What does VLDL do?
VLDL transport cholesterol and newly synthesised TG to tissues
– TGs removed from VLDL leaving LDL with a high cholesterol (taken up by cells or liver)
What does HDL do?
HDL absorbs cholesterol from cell breakdown and transfer it to VLDL and LDL
Describe lipoprotein metabolism’s impact on health
↑ plasma cholesterol associated with ↑ LDL is a risk factor for atheromatous disease
– may lead to atherosclerosis, ischaemic heart disease, myocardial infarction & cerebral vascular accidents
An increase in the plasma concentration of lipids is called hyperlipidaemia
What is an increase in the plasma concentration of lipids called?
hyperlipidaemia
What is associated with a high plasma conc. of total and LDL cholesterol?
↑ risk of atherosclerosis and CHD associated
Where in the artery wall do plaques form?
The intima
What is the average total cholesterol level in the UK?
5.7mmol/l
What is the ideal total cholesterol level?
< 5mmol/l
What are the ranges of considered cholesterol severity?
Ideal level (< 5mmol/l)
Mildly high cholesterol level (5 to 6.4mmol/l)
Moderately high cholesterol level (6.5 to 7.8mmol/l)
Very high cholesterol level (> 7.8mmol/l)
Other than total cholesterol level what factors have to be taken into account in assessing someones risk presented by cholesterol level?
– the ratio between “good” (HDL) and “bad” (LDL) cholesterol
– other risk factors for cardiovascular disease,
• e.g. smoking, diabetes, high blood pressure
What is the aim of lipid lowering drugs?
Aim is to reduce plasma cholesterol
– Lifestyle modification (i.e. diet and exercise) is first step
– Drug therapy should be secondary
How do lipid lowering drugs work?
Work either by reducing production of lipoproteins or by increasing their removal from the blood
How does the body accumulate cholesterol?
Cholesterol is derived from 3 sources
– De novo synthesis in liver
– Uptake form circulating LDLs
– Uptake of chylomicron remnants
What actions may drugs take to lower cholesterol?
Sequester bile acids in the intestine/Decrease hepatic stores of cholesterol
– e.g. colestyramine
Inhibit transport protein for cholesterol in the brush border of enterocytes in the duodenum
– e.g. ezetimibe
Alter the levels of plasma lipoproteins
– e.g. fenofibrate, bezafibrate, gemfibrozil & nicotinic acid
Inhibit the synthesis of cholesterol in the liver
– e.g. simvastatin, pravastatin, atorvastatin, rosuvastatin
What is colestyramine?
Is a basic anion exchange resin
What does colestyramine do?
– 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
How effective are bile-sequestering drugs?
Bile-sequestering drugs plus inhibitors of cholesterol biosynthesis can lower blood cholesterol by 50%
What are fibrates?
activators of lipoprotein lipase
Name some fibrates
Fenofibrate, gemfibrozol
What do fibrates do?
– ↓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
In what clinical situations may fibrates be used?
Mixed dyslipidaemia (i.e. raised serum triglyceride as well as cholesterol)
In patients with low HDL and high risk of atheromatous disease (e.g. Type 2 diabetes)
Combined with other lipid-lowering drugs in patients with severe treatment resistant dyslipidaemia
What is nicotinic acid?
(niacin)
Vitamin with lipid-lowering properties
What does nicotinic acid (niacin) do?
– ↓ VLDL production which leads to a ↓ in LDL – Also activates lipoprotein lipase
What does ezetimibe do?
Specifically reduces intestinal cholesterol absorption
– Inhibits a sterol carrier protein in the brush border of the enterocytes
What are statins?
Hydroxymethlglutamyl-coenzyme A reductase (HMG-CoA reductase) inhibitors
What is HMG-CoA reductase?
– Major rate-limiting step in cholesterol synthesis
– Converts HMG-CoA to mevalonic acid (MVA)
What are simvastatin, pravastatin, atorvastatin and rosuvastatin?
– long-lasting HMG-CoA reductase inhibitors
What is the mevalonate pathway?
One half = cholesterol synthesis
Other half = protein prenylation
What is protein prenylation?
Addition of lipid tails to small GTPase signaling molecules
Ensures they are localised correctly
(Ras and Rho)
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
Atorvastatin lowers serum cholesterol in familial hypercholesterolaemia
What are the side effects of statins?
Statins can cause myositis, angio-oedema, GI disturbances, insomnia, rash
What are the side effects of fibrates?
Fibrates can cause myositis (esp. in patients with renal impairment), GI disturbances
What are the side effects of colestyramine + ezetimibe?
Colestyramine, ezetimibe can cause GI symptoms (nausea, abdominal bloating, constipation, diarrhoea)
What are the side effects of nicotinic acid (niacin)?
Nicotinic acid can cause flushing, palpitations, GI disturbances
Name some PCSK9 inhibitors
Alirocumab and evolcumab
What do PCSK9 inhibitors do?
PCSK9 is an enzyme that 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.
