Atherosclerosis, Lipoproteins and Lipid-Lowering Drugs Flashcards

1
Q

Describe the Exogenous pathway of Lipid Metabolism:

A

Dietary triglycerides and cholesterol are broken down and packaged into Chylomicrons

These are broken down into smaller and smaller lipids and into chylomicron remnants

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2
Q

Are most of our lipids Exogenous or Endogenous?

A

Endogenous

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3
Q

What is the definition of Atherosclerosis?

A

Atherosclerosis is an inflammatory fibro-proliferative disorder

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4
Q

What are the stages of Atherosclerosis?

A

LDLs get into the endothelium

Release of Growth Factors and Cytokines

These attract Monocytes

Leads to the formation of Foam cells in the endothelium - Macrophage cells that contain lots of lipids

Proliferation of Fibroblasts and smooth muscle cells which expands the plaque

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5
Q

How is the Endothelium dysfunctional in Atherosclerosis?

A

There are a series of early changes that include

Greater Permeability

Up-regulation fo leucocytes and Endothelial adhesion molecules

Migration of Leucocytes into the endothelium

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6
Q

What is Fatty Streak formation?

A

The fatty streak is the earliest recognisable lesion of atherosclerosis

Caused by aggregation of lipid-rich foam cells
(Derived from macrophages and T-cells within the Tunica Intima)

Normally formed in the direction of blood flow
(Will later include Smooth muscle cells)

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7
Q

What is a Complicated atherosclerotic plaque?

A

A Plaque with a necrotic core formed of dead, ruptured foam cells

Smooth muscle cells migrate into the intima and lay down collagen fibres forming a fibrous cap over the lipid core

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8
Q

Why is the Fibrous cap important?

A

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

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9
Q

What is the difference between a stable and unstable atherosclerotic plaque?

A

A stable plaque has a thick vascular smooth muscle rich fiberous cap covering the necrotic lipid core

An unstable plaque has ruptured and exposes the core

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10
Q

What is an unstable atherosclerotic plaque?

A

The cap of the complicated plaque ruptures and exposes the thrombogenic lipid core to circulating platelets and coagulation factors leading to thrombosis

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11
Q

Apart from thrombosis, what else can a complicated atherosclerotic plaque lead to?

A

The plaque can erode the artery wall, hardening it.

This results in thinning of the vessel wall, leading to aneurysm and possible haemorrhage

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12
Q

What do complicated lesions often contain?

Why is this relevant?

A

Calcium - causes hardening

Can be detected on a CT of the heart

Generally believed, the more calcium, the more symptomatic

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13
Q

What may lead to rupture of the fibrous cap?

A

Associated with greater influx and activation of macrophages, accompanied by the release of matrix metalloproteinases that are involved in the breakdown of collagen

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14
Q

What is the ‘good’ type of cholesterol?

What affects the ratio?

A

HDL good - has a protective effect for the risk of atherosclerosis and CHD

HDL tends to be low when triglycerides are high

HDL is lowered by smoking, obesity and physical inactivity

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15
Q

What is the difference between Small dense LDLs and modified LDLs?

A

Modified cause more atherosclerosis than small LDLs

They can get through the endothelium more easily

(Small dense LDLs are easily oxidised into modified LDLs)

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16
Q

What is considered a very high concentration of Triglycerides?

What risk is this associated with?

A

>1000mg/dL

Very high risk of Pancreatitis

(>200mg/dL is considered high)

17
Q

What is the first-line treatment for Dyslipidaemia?

A

Statins - Highly effective in lowering LDLs and have a good tolerability profile

18
Q

Where do Statins act?

A

On the Mevalonate pathway of Cholesterol Synthesis

They inhibit HMG-CoA Reductase - preventing Mevalonic acid from being produced

19
Q

What are two important products produced during Cholesterol synthesis, and why?

A

Geranyl Pyrophosphate
Farnesyl Pyrophosphate

Small lipids that are extremely important - involved in the modification and activation of proteins

Cell can function without Cholesterol, but not these two

20
Q

How do Statins reduce elevated LDLs?

A

They block cholesterol synthesis in the liver

Liver responds by making more LDL receptors to uptake more LDLs - lowering the concentration in the blood

Circulating VLDLs also bind to the receptors, moderately reducing triglyceride levels

The Liver also produces more HDLs to carry cholesterol back from the periphery of the body

21
Q

Name 5 major Statins

Which two have considerably longer half-lives?

A

Simvastatin (1-2h)
Fluvastatin (1-2h)
Pravastatin (1-2h)

Atorvastatin (14h)
Rosuvatatin (20h)

22
Q

What is the rule of 6 with regards to Statins?

A

If you double the dose of any statin, you only get a 6% reduction in LDL cholesterol

23
Q

What are the main side-effects of Statins?

A

GI Symptoms
Rashes

Myalgia
Rhabdomyolysis

Hepatotoxic - especially in those with preexisting liver disease

Teratogenic - avoid in pregnancy

24
Q

What drugs other than Statins may be used to treat Dyslipidaemia?

A

Fibrates

Nicotinic acid

Ezetimibe

25
Q

What are Fibrates?

What is their target?
What effect do they have?
What are they often used to treat?

A

They activate PPAR-alpha receptors

Lower plasma fatty acids and triglycerides (better than statins)

Often given to diabetics with high triglycerides

26
Q

What is Ezetimibe?

What do they do?
Why may they be given?

A

A drug that inhibits cholesterol absorption

Ezetimibe is absorbed and activated as Glucuronide
They reduce LDLs

May be given alongside statins to further increase LDL reduction due to the rule of 6