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Pharmacology > Atherosclerosis and lipid metabolism > Flashcards

Atherosclerosis and lipid metabolism Flashcards

1
Q

Why is CVD and CHD becoming more common all over the world?

A

Due to the western diet

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2
Q

What is the main culprit in atherosclerosis?

A

LDL - it gets into the vascular wall to form a core of atheroma

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3
Q

What is the exogenous pathway of lipid metabolism?

A
  • Lipids enter the blood in two ways, one of which is absorption of fats from the diet
  • The amount of the cholesterol that enters the circulation from the diet is very small
  • However, other lipids (such as triglycerides) are certainly absorbed
  • Triglycerides are absorbed as chylomicrons into the blood
  • If you ingest a very fatty meal and then take a blood sample, chylomicrons are present in the plasma
  • Chylomicrons are broken down by lipases, into remnants
  • Some of this ends up as atheroma, in the vascular wall
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4
Q

What is the endogenous pathway of lipid metabolism?

A
  • There is a pathway in which the liver generates different lipoproteins, which are then broken down and converted
  • Some of the lipoproteins end up with the LDL receptor
  • This endogenous pathway forms around 80% of the cholesterol in the body
  • Most circulating lipids are endogenous
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5
Q

What is the importance of chlylomicrons in atherosclerosis?

A
  • Chylomicron remnants are lipids of lipoproteins that come about as the chylomicrons are broken down and become smaller and smaller
  • These chylomicron remnants are very good at getting into the blood vessel wall - into the tunica intima
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6
Q

What is reverse cholesterol transport?

A
  • This is a process where cholesterol is taken out of blood vessels and foam cells
  • There is a transformation of HDL (beneficial) back to LDL – by cholesteryl ester transfer protein
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7
Q

What are foam cells?

A

Smooth muscle macrophages that are full of lipid (including cholesterol)

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8
Q

How can reverse cholesterol transport be inhibited?

A

We can block CETP (cholesteryl ester transfer protein) and thus increase HDL and reduce LD

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9
Q

….

A

Atherosclerosis is an inflammatory process

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10
Q

What is the first stage in atherosclerosis?

ENDOTHELIAL DYSFUNCTION

A

ENDOTHELIAL DYSFUNCTION

  • The endothelium becomes dysfunctional
  • The endothelium is responsible for producing a lot of mediators
  • Endothelial dysfunction in atherosclerosis is characterised by a series of early changes that precede lesion formation
  • The changes include greater permeability of the endothelium, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall
  • If the endothelium is not functioning properly, it is more likely that things will get through the endothelial layer of control
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11
Q

What are the changes that occur in the endothelium before atherosclerosis?

A
  • The changes include greater permeability of the endothelium, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall
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12
Q

What happens in stage 2 of atherosclerosis?

FATTY STREAK FORMATION

A

FATTY STREAK FORMATION

  • The fatty streak is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipid-rich foam cells (derived from macrophages and T lymphocytes within the tunica intima)
  • Later on the lesions will also include smooth muscle cells
  • The fatty streaks are usually formed in the direction of blood flow
  • Most fatty streaks don’t actually develop into serious atherosclerosis
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13
Q

What happens in stage 3 of atherosclerosis?

FORMATION OF PLAQUE

A

FORMATION OF PLAQUE

  • This results from the death and rupture of the foam cells in the fatty streak
  • You get formation of a necrotic core
  • The migration of smooth muscle cells into the intima and laying down collagen fibres results in the formation of a protective fibrous cap over the lipid core
  • The fibrous cap is extremely important because it separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors
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14
Q

….

A
  • LDL moves into the subendothelium and is oxidised by macrophages and smooth muscle cells
  • You get release of growth factors and cytokines, which attract inflammatory cells such as monocytes
  • Foam cells form in the endothelium (macrophages that contain lipid, cholesterol or cholesterol esters)
  • There will also be proliferation of fibroblasts and smooth muscle cells – this expands the plaque
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15
Q

What do complicated lesion contain and how may this be detected?

A
  • Complicated lesions often contain calcium

- Coronary artery disease can be detected by doing a CT scan of the heart - this will detect any calcium

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16
Q

What is the relationship between the amount of calcium in the plaque and how bad the atherosclerosis is?

A

It is generally believed that the more calcium you have in the plaque, the more likely you are to be symptomatic

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17
Q

Where do remnants come from and why are they important?

A
  • Remnant lipids come from the chylomicrons
  • The remnant lipids are important because they are quite atherogenic
  • If there are lots of remnant lipoproteins in the blood (as a result of eating fatty meals), the individual is at a higher risk of CHD compared to blood with fewer remnants
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18
Q

Give examples of chylomicron remnants

A

VLDL, chylomicron remnant and IDL

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19
Q

How are stable atherosclerotic plaques characterised?

A

Necrotic lipid core covered by a thick vascular smooth muscle, has a thick fibrous cap

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20
Q

How are vulnerable atherosclerotic plaques characterised?

A

Vulnerable plaques are characterised by thin fibrous caps, a core rich in lipid and macrophages and less evidence of smooth muscle proliferation.

21
Q

Why would someone with a stable plaque have symptoms?

A

Due to the thick cap obstructing blood flow to the heart -> PAIN

22
Q

How could a vulnerable plaque become a thrombosis?

A

Someone with a vulnerable plaque has only a very thin wall separating the lumen and lipid core. A surge in BP could lead to the breaking down of the thin fibrous cap -> thrombosis

23
Q

How is LDL involved in atherosclerosis?

How does an increase in it affect CHD risk?

What factors aggregate the effects of LDL?

How can LDL become more atherogenic and what can protect it from this?

A
  • Strongly associated with atherosclerosis and CHD events
  • 10% increase results in a 20% increase in CHD risk
  • Low HDL cholesterol, smoking, hypertension, diabetes
  • If LDL is modified (particularly by oxidising it), it becomes much more atherogenic. HDL can protect the LDL from oxidation.
24
Q

How does HDL affect the risk of atherosclerosis?

When is HDL low?

What lowers HDL levels?

Who has lower HDL levels?

A
  • HDL cholesterol is protective for risk of atherosclerosis and CHD (promotes reverse cholesterol transport)
  • The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD
  • HDL cholesterol tends to be low when triglycerides are high
  • HDL cholesterol is lowered by smoking, obesity and physical inactivity
  • Smokers and obese people tend to have lower levels of HDL cholesterol
25
Q

What are the 5 classes of drugs used to treat dyslipidaemia?

A
  • Bile Acid Sequestrants: effective cholesterol-lowering drugs,
  • Nicotinic Acid: effective at increasing HDL cholesterol
  • Fibrates: effective triglyceride-lowering drugs
  • Probucol: only has a modest effect in lowering LDL cholesterol
    Statins: highly effective in lowering LDL cholsterol and they have a good tolerability profile, first line treatment
26
Q

Side effects of bile acid sequestrants

A

Compliance can be a problem because they tend to cause GI bloating, nausea and constipation

27
Q

Side effects of nicotinic acid

A

Flushing, skin problems, GI distress, liver toxicity, hyperglycaemia and hyperuricaemia

28
Q

Look at table for treatment specifics

A

on notes

29
Q

Where do statins acts?

A

Statins act on the mevalonate pathway to inhibit HMG-CoA Reductase

30
Q

Importance of geranyl pyrophosphate and farnesyl pyrophosphate

A

These are small lipids that are extremely important in the cell function, because they are involved in the modification and activation of proteins. So they are involved in cell growth, proliferation etc. The cell can’t function properly without these lipids.

31
Q

What happens if you block cholesterol synthesis in the liver?

A
  • The liver cells respond by making more LDL receptors

- These LDL receptors bind to circulating LDL and lower it

32
Q

Do all statins have the same potency?

A

No, although all of these drugs block the same enzyme, they do not do it with the same potency

33
Q

What does the selectivity ratio show?

A

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

34
Q

What does the potency number mean?

A

The lower the number the more powerful the drug as an inhibitor of the enzyme

35
Q

What is the effect of statins on lipids? How does changing dose affect the level of LDL?

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. The effectiveness of statin treatment depends on the level of cholesterol that you achieve - the lower the cholesterol, the lower the risk for the patient

36
Q

LDL and cardiovascular risk

A
  • Studies have shown that the reduction in cardiovascular risk is directly proportional to the amount by which LDL is lowered. This is not to say that LDL is the only factor in risk, but it seems to be an essential, indispensable factor.
37
Q

Statins in people with a risk of CVD

A
  • Statins improve survival and reduce risk in people without established cardiovascular disease
  • It doesn’t matter about age, sex or diabetic status
  • People at increased risk for CVD should not be denied the relative benefits of long-term statin use
38
Q

What are pleotropic effects of stations?

A

Effects that are not directly related to the reduction in cholesterol.

39
Q

Statins in inflammatory processes

A
  • Statins are anti-inflammatory in a vascular setting
  • They can be anti-inflammatory in other situations too (e.g. rheumatoid arthritis, IBD)
  • It has been proposed that using statins in chronic inflammation will be useful
40
Q

What do fibrates do?

A
  • Main mechanism of action is activation of PPAR alpha receptors (nuclear receptors)
  • Fibrates lower plasma fatty acids and triglycerides (they are much better than statins are doing this)
  • Fibrates reduce inflammation
  • A study gave fibrates to patients with low HDL AND low LDL
  • The patients showed improvement despite only HDL increasing (LDL remained the same)
41
Q

What is PPAR?

A

PPAR = peroxisome proliferator activated receptors

42
Q

PPAR gamma activators

A

PPAR gamma activators are the thiazolidinediones (glitazones) used in diabetes

43
Q

What does nicotinic acid do?

Why isn’t it used much in clinical practice?

A
  • It lowers LDL, it increases HDL, it lowers triglycerides and increases fibrinolytic activity (clot dissolution)
  • This is because it is not well tolerated (causes flushing, so it isn’t taken by patients)
44
Q

What does ezetimibe do?

A
  • Inhibits cholesterol absorption
  • Ezetimibe is absorbed and then activated as glucuronide
  • They reduce LDL cholesterol a reasonable amount (15-20%)
  • Ezetimibe decreases LDL further when given with a statin
45
Q

CETP inhibitors - torcetrapib

A
  • A drug was developed that blocked CETP and had positive effect in increasing HDL and decreasing LDL
  • However, when they expanded the clinical trial they found that it was actually killing people
  • There were ‘off-target’ adverse effects of
  • It might be due to activation of aldosterone synthesis leading to increased blood pressure
  • Other ‘rapibs’ do not have the same effects
46
Q

What are off target effects?

A

You could not have predicted this effect from the properties of the drug

47
Q

PCSK9 - Proporotein convertase subtilisin/kexin type 9 inhibition

A
  • PCSK9 is an inhibitor of the LDL receptor so it stops the LDL from reaching the LDL receptor
  • LDLR and PCSK9 gene expression are coinduced by statins
  • As a result, PCSK9 inhibition enhances the lipid-lowering effect statins
  • Monoclonal antibodies are the most advanced PCSK9 inhibitors currently in development (they inactive PCSK9)
  • It protects the LDL receptor so that the LDL receptor can continue to work well
48
Q

PCSK9 inhibitor and atorvastatin

A
  • PCSK9 inhibitors given with atorvastatin causes a big decline in cholesterol
  • Familial hypercholesterolemia patients appear to have the greatest need for such therapies.

Pharmacology (26 decks)

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