Cholesterol Lowering Drugs

Question 1

Describe the structure of lipoproteins

Answer 1

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

Question 2

Name the five main classes of lipoproteins

Answer 2

High density lipoproteins (HDL)
Intermediate density lipoproteins (IDL)
Low density lipoproteins (LDL)
Very low density lipoproteins (VLDL)
Chylomicrons

Question 3

Describe the exogeneous pathway for forming cholesterol

Answer 3

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.

Question 4

What is the role of VLDL?

Answer 4

It transports cholesterol and triglycerides to tissues. The triglycerides are removed by lipoprotein lipase leaving LDL with a high cholesterol.

Question 5

What is the role of HDL

Answer 5

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.

Question 6

Describe the endogenous pathway for the synthesis of cholesterol

Answer 6

It uses acetyl CoenzymeA which is converted to MVA by HMG-CoA reductase, which can then be turned into cholesterol.

Question 7

How can cholesterol be removed?

Answer 7

Via bile acids which are then excreted in faeces

Question 8

Increased plasma cholesterol and increased LDL is a risk factor for what? and may lead to whay?

Answer 8

Risk factor for atheromatous disease which may lead to atherosclerosis, ischaemic heart disease, myocardial infarction and cerebral vascular accidents.

Question 9

What is hyperlipidaemia?

Answer 9

An increase in plasma concentration of lipids

Question 10

What is the ideal cholesterol level?

Answer 10

<5mmol/l

Question 11

Describe basically, how lipid lowering drugs work?

Answer 11

They work by either reducing production of lipoproteins or by increasing their removal from the blood

Question 12

Describe the four different actions of cholesterol lowering drugs

Answer 12

• 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

Question 13

Describe what Colestryamine is and how it works

Answer 13

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

Question 14

Name two examples of drugs in the class Fibrates

Answer 14

Fenofibrate and Gemfibrozol

Question 15

How do the fibrates work?

Answer 15

• 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.

Question 16

What are some of the clinical uses of fibrates

Answer 16

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.

Question 17

Describe how nicotinic acid (niacin) works

Answer 17

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

Question 18

Describe how Ezetimibe works

Answer 18

It specifically reduced intestinal cholesterol absorption. It does this by inhibiting a sterol carrier protein in the bush boarder of the enterocytes

Question 19

Name some examples Statins

Answer 19

Simvastatin, Pravastatin, atorvastatin and rosuvastatin

Question 20

Describe how Statins work

Answer 20

They are long lasting HMG-CoA reductase inhibitors

Question 21

What does HMG-CoA reductase do?

Answer 21

It is involved in the major rate-limiting step in cholesterol synthesis. It works by converting HMG-CoA into Mevalonic acid (MVA)

Question 22

What does the Mevalonate pathway produce?

Answer 22

One half is involved in cholesterol synthesis and the other half is involved in protein prenylation

Question 23

What is protein prenylation?

Answer 23

Addition of lipid tails to small GTPase signalling molecules

Question 24

What are some of the clinical uses of statins?

Answer 24

Secondary prevention of myocardial infarctions and strokes in patients with atherosclerosis.
Primary prevention of arterial disease
Atorvastatin lowers serum cholestrol in familial hypercholestrolaemia

Question 25

What are some of the side effects of statins?

Answer 25

GI disturbances, myositis, angio-oedema, insomnia and rash

Question 26

What are some of the side effects of fibrates

Answer 26

Myositis and GI disturbances

Question 27

What are some of the side effects of colestyramine and ezetimibe?

Answer 27

GI symptoms such as nausea, bloating, constipation or diarrhoae

Question 28

What are some of the symptoms of Nicotinic acid?

Answer 28

Flushing, palpitations and GI disturbances.