Cholesterol Lowering Drugs Flashcards
Describe the structure of lipoproteins
It has a central core consisting of triglycerides and cholesterol esters with a hydrophilic coat composed of phospholipids, free cholesterol and associated proteins (apoproteins and apolipoproteins
Name the five main classes of lipoproteins
High density lipoproteins (HDL) Intermediate density lipoproteins (IDL) Low density lipoproteins (LDL) Very low density lipoproteins (VLDL) Chylomicrons
Describe the exogeneous pathway for forming cholesterol
Fatty acids and cholesterol are absorbed by the gut wall into the lymphatics where they are transported by Chylomicrons. The chylomicrons are split lipoprotein lipase to release the free fatty acids. The chylomicron is then endocytosed by liver cells where the cholesterol is stored, oxidised to bile acids or released to VLDL.
What is the role of VLDL?
It transports cholesterol and triglycerides to tissues. The triglycerides are removed by lipoprotein lipase leaving LDL with a high cholesterol.
What is the role of HDL
It absorbs cholesterol from cell breakdown and transfers it too VLDL and LDL which can transport the cholesterol back to the liver or the HDL can transport the cholesterol back to the liver itself.
Describe the endogenous pathway for the synthesis of cholesterol
It uses acetyl CoenzymeA which is converted to MVA by HMG-CoA reductase, which can then be turned into cholesterol.
How can cholesterol be removed?
Via bile acids which are then excreted in faeces
Increased plasma cholesterol and increased LDL is a risk factor for what? and may lead to whay?
Risk factor for atheromatous disease which may lead to atherosclerosis, ischaemic heart disease, myocardial infarction and cerebral vascular accidents.
What is hyperlipidaemia?
An increase in plasma concentration of lipids
What is the ideal cholesterol level?
<5mmol/l
Describe basically, how lipid lowering drugs work?
They work by either reducing production of lipoproteins or by increasing their removal from the blood
Describe the four different actions of cholesterol lowering drugs
- Isolate bile acids in the intestine/decrease hepatic stores of cholesterol
- Inhibit transport protein for cholesterol in the bush boarder of enterocytes in the duodenum
- Alter the levels of plasma lipoproteins
- Inhibit the synthesis of cholesterol in the liver
Describe what Colestryamine is and how it works
It is a cholesterol lowering drug. It works by isolating bile acids to prevent enterohepatic recirculation and therefore increases the metabolism of endogenous cholesterol into bile acids. It also increases the number of LDL receptors in the liver resulting in the removal of LDLs from the blood
Name two examples of drugs in the class Fibrates
Fenofibrate and Gemfibrozol
How do the fibrates work?
- Main action is stimulation of lipoprotein lipase which decreases triglyceride content of VLDL
- Decrease the plasma tryglycerides and slightly decrease cholesterol
- Decrease elevated concs of VLDL
- Clearance of LDL by liver is stimulated
- Increased HDL production and reverse cholesterol transport.
What are some of the clinical uses of fibrates
In patients with mixed dyslipidaemia (raised serum triglyceride + cholesterol)
In patients with low HDL and high risk of atheromatous disease (type2 diabetics)
In combo with other lipid lowering drugs in patients with resistant dyslipidaemia.
Describe how nicotinic acid (niacin) works
It is a vitamin with lipid-lowering properties. It works by reducing VLDL production which leads to a decrease in LDL.
It also activates lipoprotein lipase
Describe how Ezetimibe works
It specifically reduced intestinal cholesterol absorption. It does this by inhibiting a sterol carrier protein in the bush boarder of the enterocytes
Name some examples Statins
Simvastatin, Pravastatin, atorvastatin and rosuvastatin
Describe how Statins work
They are long lasting HMG-CoA reductase inhibitors
What does HMG-CoA reductase do?
It is involved in the major rate-limiting step in cholesterol synthesis. It works by converting HMG-CoA into Mevalonic acid (MVA)
What does the Mevalonate pathway produce?
One half is involved in cholesterol synthesis and the other half is involved in protein prenylation
What is protein prenylation?
Addition of lipid tails to small GTPase signalling molecules
What are some of the clinical uses of statins?
Secondary prevention of myocardial infarctions and strokes in patients with atherosclerosis.
Primary prevention of arterial disease
Atorvastatin lowers serum cholestrol in familial hypercholestrolaemia
What are some of the side effects of statins?
GI disturbances, myositis, angio-oedema, insomnia and rash
What are some of the side effects of fibrates
Myositis and GI disturbances
What are some of the side effects of colestyramine and ezetimibe?
GI symptoms such as nausea, bloating, constipation or diarrhoae
What are some of the symptoms of Nicotinic acid?
Flushing, palpitations and GI disturbances.
