Atherosclerosis, lipoproteins and lipid lowering drugs

Question 1

Which are the ‘bad’ and ‘good’ cholesterol forms?

Answer 1

• Good = HDL
• Bad = LDL

Question 2

Outline the exogenous pathway of lipid metabolism and what parts are atherogenic?

Answer 2

• Dietary cholesterol intake
• Dietary tryglyceride intake → transported as chylomicrons → broken down by lipoprotein lipase enzymes into free fatty acids and chylomicron remnants
• The chylomicron remnants contribute to the atheroma

Question 3

Outline the endogenous pathway components, and mention briefly which components are atherogenic

Answer 3

• Liver generates large VLDLs, small VLDLs and IDLs using hepatic lipase
• Lipoprotein lipase converts large VLDLs into small VLDLs and small VLDLs into IDLs an IDLs into LDLs
• IDL and more so LDLs can enter the tunica intima and contribute to the fatty lipid core of the atherosclerotic plaque

Question 4

1) What are foam cells?
2) How are foam cells formed?

Answer 4

1) Smooth muscle macrophages that are full of lipid
2) Monocytes are converted into macrophages, and once macrophages ingest lots of lipid, they become foam cells

Question 5

What is reverse cholesterol transport?

Answer 5

• Where cholesterol is removed from blood vessels and foam cells
• Conducted by HDLs

Question 6

How is HDL converted into LDLs and why is this process an important target therapeutically?

Answer 6

• HDL is converted into LDL by cholesteryl ester transport protein
• Because HDL is good because it promotes reverse cholesterol transport and LDL is bad because it contributes to the lipid core and is therefore atherogenic
• You can target the cholesteryl ester transport proteins to prevent this conversion

Question 7

Describe the pathophysiological steps in the development of atherosclerosis

Answer 7

STEP 1:

• Endothelial dysfunction
• Greater endothelial permeability
• Up-regulation of leucocytes
• Up-regulation of endothelial adhesion molecules
• Migration of leucocytes into the artery wall - particularly into the tunica intima

STEP 2:

• Fatty streak formation
• Aggregation of foam cells within the tunica intima (macrophages which ingest lots of lipids)
• Activation of T-cells
• Migration of smooth muscle cells
• SM cells and macrophages oxidise the LDLs

STEP 3:

• Atherosclerotic plaque formation
• Death and rupture of the foam cells within the fatty streak forming a necrotic core which is thrombogenic and lipid-rich
• The smooth muscle cells which have migrated here and fibroblasts at the tunica intima hyperproliferate and lay down collagen fibres respectively to form a protective fibrous cap which covers this thrombogenic necrotic, lipid-rich core and protects it from circulating platelets and coagulation factors

Question 8

What are stable and unstable atherosclerotic plaques?

Answer 8

• Stable atherosclerotic plaques have THICK fibrous caps covering the thrombogenic necrotic / lipid-rich core
• Unstable atherosclerotic plaques have THIN fibrous caps and less smooth muscle proliferation and migration at the tunica intima

Question 9

What are the dangers / downsides of…..

1) Stable atherosclerotic plaques?
2) Unstable atherosclerotic plaques?

AND WHY for each

Answer 9

1)

• The thick fibrous cap can be obstructive to blood flow to the heart and therefore can cause pain

2)

• The thin fibrous cap makes the atherosclerotic plaque very vulnerable to being ruptured
• If there is a sudden surge in BP for example, this could break the thin fibrous cap and cause thrombosis

Question 10

Explain the physiology behind how plaques can rupture

Answer 10

• Greater influx and activation of macrophages → matrix metalloproteinases
• These matrix metalloproteinases cause breakdown of collagen in the fibrous cap. Thereby causing atherosclerotic plaque rupture

Question 11

Why does someone who eats a very high lipid diet frequently have a higher chance of developing CHD?

Answer 11

• Because lipids are digested and then transported as chylomicrons
• Remember that chylomicrons are then broken down by lipoprotein lipases to form free fatty acids and chylomicron remnants
• The chylomicron remnants can contribute to the necrotic / lipid-rich core
• So higher chance or frequency of development of athersclerotic plaques, so higher risk of CHD

Question 12

How can you detect coronary artery disease using radiological imaging?

Answer 12

• CT scans of the heart can detect calcium
• Calcium is a component of complex atherosclerotic plaques which are present in coronary artery disease
• In fact the higher amount of calcium present in the plaques, the higher the risk of symptom development

Question 13

What form of LDL is very atherogenic and how does HDL have a protective effect in this sense?

Answer 13

• Oxidised LDLs are highly atherogenic
• HDLs prevent oxidisation of LDLs

Question 14

What is the first line treatment for dyslipidaemia?

Answer 14

• Statins

Question 15

1) What do bile-acid sequestrant drugs do?
2) What side effects may they have?

Answer 15

1)

• Cholesterol-lowering drugs

2)

• Bloating
• Nausea
• Constipation

Question 16

1) What do nicotinic acid drugs do?
2) What is the main side effects it causes?

Answer 16

1)

• Increase HDLs
• Lower LDLs
• Lowers plasma fatty acids
• Induces fibrinolytic activity - reduces risk fo thrombus formation

2)

• Flushing - you go red

Question 17

1) What do fibrate drugs do?
2) What is the mechanism of action of fibrates?

Answer 17

1)

• Lower plasma fatty acids and triglyceride levels
• Higher HDLs
• Reduce inflammation

2)

• Activate PPAR alpha receptors
• PPAR = Peroxisome Proliferator Activated Receptors

Question 18

What does the drug Probucol do?

Answer 18

• Modest effect in lowering LDL cholesterol

Question 19

What are the mechanisms of action of statins in lowering cholesterol and LDLs?

Answer 19

• HMG CoA reductase inhibitors
• Preventing conversion of HMG-CoA into mevalonic acid in the cholesterol pathway thereby preventing cholesterol synthesis
• When you block cholesterol synthesis, the liver upregulates LDL receptors, which bind circulating LDL and lower it

Question 20

What parts of the cholesterol synthesis pathway are important in protein modification and activation?

Answer 20

• Geranyl pyrophosphate
• Farnesyl pyrophosphate

Question 21

Statins mostly all are HMG-CoA reductase inhibitors, when comparing the pharmacological properties of statins what 2 parameters must you look at, what are they, and will they be higher or lower values to give better effects?

Answer 21

1. Selectivity ratio

• Indicates concentration of statin at the liver
• The higher the selectivity ratio, the higher the concentration at the liver

2. Potency

• What it says on the tin
• The lower the number, the more powerful the drug as an inhibitor of HMG-CoA reductase

Question 22

What does the rule of 6 refer to when it comes to statins?

Answer 22

• If you double the dose of statins, you only get a 6% reduction in LDL

Question 23

1) What does ezitimibe do?
2) How is ezitimibe activated?

Answer 23

1)

• Inhibits cholesterol absorption
• Lowers LDLs

2)

• Activated as glucuronide

Question 24

1) What do CETP inhibitors do / why might they be useful as therapeutic agents?
2) Name an example CETP inhibitor
3) Why are they not actually used, despite their therapeutic advantages?

Answer 24

1)

• Inhibit the cholesteryl ester transport protein which otherwise converts HDL into LDL
• Thereby preserving HDL levels and preserving the beneficial effects of HDL which include the reverse transport effect that HDL has in removing LDLs from the peripheries and back into the liver and also preventing oxidation of LDLs

2)

• Torcetrapib

3)

• It had off-target (unpredictable) effects that proved fatal

Question 25

1) What is proprotein convertase subtilisin / kexin type 9 inhibition, what therapeutic benefit does it have and how?
2) What drugs are they coadministered with and what type of patients is it most useful in?

Answer 25

1)

• PCSK9 normally inhibits the LDL receptors which otherwise bind LDLs and prevent them depositing in peripheries
• Therefore PCSK9 inhibitors which are usually monoclonal antibodies that inactivated PCSK9 promote LDL receptors to lower LDL levels

2)

• They are co-administered with statins to hae a greater effect
• This is because statins also upregulate LDL receptors as part of their actions in lowering LDL levels
• So by further promoting the LDL receptors using the PCKS9 inhibitors, you have a great effect on the levels of LDLs in the blood
• Useful in patients with familial hypercholesterolaemia

Question 26

Give 5 drugs which might be given as well as statins in order to lower LDL levels

Answer 26

1. CETP inhibitors
2. Ezitimibe
3. Fibrates
4. Nicotinic acid
5. PCSK9 inhibitors