Cholesterol Lowering Drugs

Question 1

Describe the structure of lipoproteins.

Answer 1

• Central core of hydrophobic lipid (triglycerides or cholesterol esters)
• Hydrophilic coat of polar substances (phospholipids, free cholesterol, associated proteins)

Question 2

What are the main types of associated proteins which may be found in the hydrophilic coat of lipoproteins.

Answer 2

Apoproteins and apolipoproteins

Question 3

What is the main function of lipoproteins ?

Answer 3

Transporting fats, lipids, and cholesterol in blood

Question 4

What are the main classes of lipoproteins ?

Answer 4

1) High density lipoproteins (HDL) = good cholesterol
2) Intermediate density lipoproteins (IDL)
3) Low density lipoproteins (LDL) = bad cholesterol
4) Very low density lipoproteins (VLDL)
5) Chylomicrons

Question 5

What are the factors which distinguish the five classes of lipoproteins ?

Answer 5

– core lipids
– apoproteins (e.g. HDL and LDL have different ones)
– size
– density

Question 6

Which classes of cholesterol are associated with which pathway ?

Answer 6

ENDOGENOUS PATHWAY: 
High density lipoproteins (HDL) 
Intermediate density lipoproteins 
Low density lipoproteins (LDL) 
Very low density lipoproteins (VLDL)

EXOGENOUS PATHWAY:
Chylomicrons

Question 7

Rank all classes of cholesterol by size, smallest to largest.

Answer 7

HDL (smallest) < LDL < IDL < VLDL < Chylomicron

Question 8

Describe the main features of the endogenous pathway.

Answer 8

-Basically: Taking cholesterol (also triacyl glycerols, free FAs) that is synthesised in liver and distributing it in body or returning it from sites of body to the liver

• Specifically:
  1) VLDL transport cholesterol and newly synthesised TG to tissues (TG > cholesterol)
  2) VLDL transports TG and cholesterol from liver to tissues (they are split through hydrolysis by lipoprotein lipase to release free fatty acids (FFAs. FFAs taken up by muscle and adipose tissue)
  3) TGs removed from VLDL leaving LDL with a high cholesterol (taken up by liver through endocytosis using LDL receptors in liver or by tissues)
  4) HDL absorbs cholesterol from cell breakdown (from tissues) and transfer it to VLDL and LDL for return back to the liver

Question 9

Describe the main features of the exogenous pathway.

Answer 9

-Basically: Taking cholesterol (also triacyl glycerols, free FAs) from diet (from GI system) and take it to liver for distribution and processing.

• Specifically :
  1) Cholesterol, triglycerides uptaken from GI system into chylomicrons (TG > cholesterol)
  2) Chylomicrons transport TG and cholesterol esters from the GI (diet) to tissues (they are split through hydrolysis by lipoprotein lipase to release free fatty acids (FFAs. FFAs taken up by muscle and adipose tissue)
  3) Now cholesterol > TG in the chylomicron. Hence, chylomicron remnants taken up in the liver (cholesterol stored, oxidised to bile acids or released to VLDL)

Question 10

What does a high HDL and a high LDL suggest respectively, wrt to levels of cholesterol in the liver, and in the circulation.

Answer 10

High levels of LDL suggests high levels of circulating cholesterol
High levels of HDL suggests cholesterol is being taken back to liver

Question 11

Does the level of LDL alone give sufficient information about state of health ? Explain why or why not.

Answer 11

No, because for instance high both LDL and HDL may be having a beneficial effect but if only LDL is high than may have a problem.

Question 12

What are the main functions of cholesterol ?

Answer 12

Production of Bile Acids
Hormone Production
Support of Cell Membrane

Question 13

What is the function of bile acids ?

Answer 13

“Facilitate the digestion and absorption of fats and fat-soluble molecules in the intestine, and to keep cholesterol from precipitating in bile”

Question 14

What, in relation to cholesterol, is a risk factor of atheromatous disease and Coronary Heart Disease ?

Answer 14

High plasma concentration of total and LDL cholesterol

Question 15

What specific atheromatous diseases may high plasma total and LDL cholesterol lead to ?

Answer 15

Atherosclerosis, ischaemic heart disease, myocardial infarction & cerebral vascular accidents

Question 16

What is high LDL and total plasma cholesterol a risk factor for ?

Answer 16

Atheromatous diseases, including atherosclerosis, ischaemic heart disease, myocardial infarction & cerebral vascular accidents
Coronary Heart Disease

Question 17

What is hyperlipidaemia ?

Answer 17

Increase in the plasma concentration of lipids

Question 18

What are the ideal levels of cholesterol ? Mildly high cholesterol ? Moderately high cholesterol ? Very high cholesterol ?

Answer 18

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)

Question 19

What is the average level of cholesterol in the UK ?

Answer 19

5.7mmol/l

Question 20

What are other important factors to take into account when assessing the risk for cardiovascular disease, besides cholesterol levels ?

Answer 20

– the ratio between “good” (HDL) and “bad” (LDL) cholesterol
– other risk factors for cardiovascular disease,
• e.g. smoking, diabetes, high blood pressure

Question 21

How do lipid-lowering drugs work, in general ?

Answer 21

Aims to reduce plasma cholesterol, by either of the following:

• by reducing production of lipoproteins
• by increasing their removal from the blood

Question 22

What treatment options exist to lower lipid levels ?

Answer 22

• Lifestyle modifications first and foremost (diet, exercise)
• Drug therapy should be secondary

Question 23

Where is cholesterol derived from ?

Answer 23

– De novo synthesis (newly synthesised) in liver
– Uptake from circulating LDLs
– Uptake of chylomicron remnants

Question 24

What are the main classes of lipid-lowering drugs ? How does each work ?

Answer 24

Sequester bile acids in the intestine/Decrease hepatic stores of cholesterol
– e.g. bile acid sequestrants

Enhance the removal of LDL
– e.g. PCSK9 inhibitors

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. fibrates

Inhibit the synthesis of cholesterol in the liver
– e.g. statins, bempedoic acid

Question 25

Describe the actions of Colestyramine.

Answer 25

-Colestyramine is a basic anion exchange resin
- sequesters bile acids to prevent enterohepatic
recirculation (cannot be recycled and just excreted out in faeces)
- ∴↑the metabolism of endogenous cholesterol into bile acids (cholesterol concentration in liver goes dow)
- ↑ LDL receptor numbers in the liver resulting in the removal of LDLs from the blood (cholesterol from body taken to liver)

Bile-sequestering drugs plus inhibitors of cholesterol biosynthesis (statins) can lower blood cholesterol by 50% (by itself not especially effective)

Question 26

Describe the actions of Fenofibrate and gemfibrozol (both Fibrates).

Answer 26

– Decrease plasma triglycerides and, to a lesser extent, cholesterol (particularly decrease elevated concentrations of VLDL)
– Main action is stimulation of lipoprotein lipase
which decrease the triglyceride content of VLDL
– Clearance of LDL by the liver is also stimulated
– Increase HDL production and reverse cholesterol transport (HDL passes cholesterol to LDL so cholesterol can return to liver)

Question 27

What are the clinical uses of Fibrates ?

Answer 27

1. Mixed dyslipidaemia (i.e. raised serum triglyceride as well as cholesterol)
2. Combined with statins in patients with low HDL and high risk of atheromatous disease (e.g. due to Type 2 diabetes)
3. Combined with other lipid-lowering drugs (mainly statins) in patients with severe treatment resistant dyslipidaemia

Question 28

Describe the actions of Nicotinic Acid (=Niacin).

Answer 28

– ↓ VLDL production which leads to a ↓ in LDL

– Also activates lipoprotein lipase (since it is a Fibrate)

Question 29

Describe the actions of Ezitimibe.

Answer 29

– Specifically reduces intestinal cholesterol absorption

– Inhibits a sterol carrier protein in the brush border of the enterocytes

Question 30

Describe the actions of Statins.

Answer 30

– Hydroxymethlglutamyl-coenzyme A reductase (HMG-CoA reductase) inhibitors
– HMG-CoA reductase catalyses conversion of HMG-CoA to mevalonic acid (MVA), which is a major rate-limiting step in cholesterol synthesis
-As a result of inhibition of ^, LDL receptors in liver are upregulated (start removing LDL from circulation)

Question 31

What are the main classes of statins ?

Answer 31

1) Lipophilic class (easy to go across cell membranes.
readily absorbed and get in high concentrations to liver and at relatively good concentrations around body)

2) Hydrophilic class (needs transporter)

Question 32

Give examples of statins. What is their duration of action ?

Answer 32

Simvastatin (usually one of choice), pravastatin, atorvastatin and rosuvastatin

Long-lasting HMG-CoA reductase inhibitors

Question 33

Identify the side effects of each class of lipid-lowering drugs.

Answer 33

Statins - Myositis, angio-oedema, GI disturbances, insomnia, rash. Strictly contra-indicated in pregnancy.

Bempedoic acid – Anaemia, gout, hyperuricaemia.

PCSK9 inhibitors – Flu-like symptoms, muscle pain.

Fibrates - Myositis (esp. in patients with renal impairment), GI disturbances.

Colestyramine, ezetimibe - GI symptoms (nausea, abdominal bloating, constipation, diarrhoea).

Question 34

What are clinical uses of statins ?

Answer 34

1) Primary prevention of arterial disease in patients with high serum cholesterol
2) Secondary prevention of myocardial infarction and stroke in those who have atherosclerotic diseases
3) Atorvastatin lowers serum cholesterol in familial hypercholesterolaemia

Question 35

Describe the Mevalonate Pathway.

Answer 35

HMG CoA (this step cayalysed by HMG CoA reductase, and blocked by statins) –> Mevalonate —–> at certain point, splits between cholesterol synthesis and protein prenylation

One half of Mevalonate pathway = cholesterol synthesis
Other half of Mevalonate pathway = protein prenylation (Addition of lipid tails to small GTPase signaling molecules such as Ras and Rho, Ensures they are localised correctly)

Question 36

How does bempedoic acid work

Answer 36

Bempedoic acid
– Reduces cholesterol synthesis in the liver by inhibiting ATP citrate lyase (which converts citrate to acetyl-CoA).