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LCRS Pharmacology and Therapeutics > Atherosclerosis and lipometabolism > Flashcards

Atherosclerosis and lipometabolism Flashcards

1
Q

How do HDLs and LDLs compare in terms of structures?

A

The components are very similar but the apoprotein is quite different and this is the factor that gives the major properties

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2
Q

How are dietary triglycerides and cholesterol metabolised?

A

They are broken down and packaged into chylomicrons
Chylomicrons are then broken down into smaller and smaller lipids and into chylomicron remnants- these products can end up in the adipose tissue and blood vessels

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3
Q

Where do most circulating lipids come from?

A

They are endogenous

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4
Q

Where does a small proportion of lipids end up?

A

In the walls of blood vessels

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5
Q

What are chylomicron remnants very good at?

A

Getting into the blood vessel wall- into the tunica intima

They’re very important in the process of atherosclerosis

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6
Q

What is atherosclerosis?

A

An inflammatory fibre-proliferative disorder

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7
Q

What is the first stage of atherosclerosis development?

A

LDLs get into the endothelium

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8
Q

What happens once LDLs get into the endothelium?

A

You get release of growth factors and cytokines which attract inflammatory cells such as monocytes
Formation of foam cells in the endothelium
Proliferation of fibroblasts and smooth muscle cells- expands the plaque

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9
Q

What are foam cells?

A

Macrophages that contain a lot of lipid

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10
Q

What changes occur that characterise endothelial dysfunction that precede lesion formation?

A

Greater permeability of endothelium
Up-regulation of leucocytes and endothelial adhesion molecules
Migration of leucocytes into the artery wall

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11
Q

What does the endothelium normally do?

A

It is an active line of cells that makes growth factors and inflammatory mediators etc

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12
Q

What is the earliest recognisable lesion of atherosclerosis?

A

The fatty streak

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13
Q

What causes the fatty streak?

A

Aggregation of lipid-rich foam cells (derived from macrophages and T lymphocytes within the tunica intima)

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14
Q

What do the lesions include later on after the fatty streak?

A

Smooth muscle cells

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15
Q

In what way are fatty streaks usually formed?

A

In the direction of blood flow

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16
Q

What causes the formation of a complicated atherosclerotic plaque?

A

Death and rupture of foam cells in the fatty streak- formation of a necrotic core

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17
Q

What causes formation of the fibrous cap in a complicated atherosclerotic plaque?

A

Migration of smooth muscle cells into the intimate and laying down collagen fibres results in the formation of a protective fibrous cap over the lipid core

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18
Q

Why is the fibrous cap extremely important?

A

It separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors

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19
Q

What are stable atherosclerotic plaques characterised by?

A

A necrotic lipid core covered by a thick vascular smooth muscle-rich fibrous plaque

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20
Q

What happens when an atherosclerotic plaque becomes unstable?

A

The plaque ruptures and exposes the thrombogenic lipid rich core to the circulating platelets and coagulation factors which leads to thrombosis

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21
Q

What else can plaque erosion cause?

A

Hardening of the arteries which results in weakening and thinning of vessel wall leading to aneurysm and possible haemorrhage

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22
Q

What do complicated atherosclerotic lesions often contain?

A

Calcium

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23
Q

How can coronary artery disease be detected?

A

By doing a CT scan of the heart- detects any calcium

24
Q

What characterises a vulnerable plaque?

A

Thin fibrous caps
Core rich in lipid and macrophages
Less evidence of smooth muscle proliferation

25
Q

What is the plaque rupture associated with?

A

Greater influx and activation of macrophages accompanied by the release of matrix metalloproteinases

26
Q

What are matrix metalloproteinases involved with?

A

Breakdown of collagen

27
Q

What lowers HDL cholesterol?

A

Smoking and obesity

28
Q

What type of lipoproteins are easily oxidised?

A

Small dense LDLs

29
Q

What type of LDLs cause a lot of atherosclerosis?

A

Modified LDLs- they can also get through endothelium more easily

30
Q

What are people with very high triglyceride levels at high risk of?

A

Pancreatitis

31
Q

What is the first line treatment for dyslipidaemia?

A

Statins

32
Q

What do bile acid sequestrants do?

A

Lower cholesterol

33
Q

What is the problem with bile acid sequestrates?

A

Compliance can be a problem as they cause GI bloating, nausea and constipation

34
Q

What does nicotinic acid do?

A

Increase HDL cholesterol

35
Q

What are the adverse actions of nicotinic acid?

A 
Flushing
Skin problems
GI distress
Liver toxicity
Hyperglycaemia
Hyperuricaemia
36
Q

What do fibrates do?

A

Lower triglycerides

37
Q

What does probucol do?

A

Modest effect at lowering LDL cholesterol

38
Q

What do statins do?

A

Highly effective at lowering LDL cholesterol

39
Q

What do statins act on?

A

The mevalonate pathway to inhibit HMG-CoA reductase

40
Q

What are two main products of this pathway that are involved in the modification and activation of proteins?

A

Geranyl pyrophosphate and farnesyl pyrophosphate- small lipids

41
Q

Can the cell function without geranyl pyrophosphate and farnesyl pyrophosphate or cholesterol?

A

Can’t function without the lipids but can function without cholesterol

42
Q

What happens if you block cholesterol synthesis in the liver?

A

The liver cells respond by making more LDL receptors which then bind to circulating LDL and lower it

43
Q

Why is the selectivity ratio important?

A

The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell

44
Q

What is the important rule of 6 in regards to statins?

A

If you double the dose of any of the statins, you only get a 6% reduction in LDL cholesterol- this applies to all statins and all doses

45
Q

What are the side effects of statins?

A

Pleiotropic- present in some but not others

Also has anti-inflammatory action

46
Q

What do fibrates do?

A

Activate PPAR-alpha receptors

47
Q

What does PPAR stand for?

A

Peroxisome proliferator activated receptors

48
Q

What is an example of a PPAR gamma activator and what is it used to treat?

A

Thiazolidinediones used in type 2 diabetes

49
Q

What effect do fibrates have?

A

They lower plasma fatty acids and lower triglycerides- better than statins

50
Q

Who are fibrates often used in?

A

Diabetics with high triglycerides

51
Q

What does ezitimibe do?

A

Inhibits cholesterol absorption- it is absorbed and then activated as glucuronide

52
Q

How is ezitimibe commonly given?

A

As an additional treatment to statins- it decreases LDL further

53
Q

Which pathway is responsible for breaking down HDL and converting it to LDL?

A

Reverse cholesterol transport

54
Q

What protein is responsible for reverse cholesterol transport?

A

CETP- cholesterol ester transfer protein

55
Q

What happened when a drug was made that inhibited CETP?

A

It had a positive effect on increasing HDL and decreasing LDL but it was actually killing people- probably due to increased activation of aldosterone synthesis leading to increased blood pressure

56
Q

What is PCSK9?

A

Inhibitor of LDL receptor so stops LDL from reaching the LDL receptor- Monoclonal antibodies have been produced that inactivate this

LCRS Pharmacology and Therapeutics (33 decks)

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