Atherosclerosis, Lipoproteins and Lipid-Lowering Drugs Flashcards
Describe the Exogenous pathway of Lipid Metabolism:
Dietary triglycerides and cholesterol are broken down and packaged into Chylomicrons
These are broken down into smaller and smaller lipids and into chylomicron remnants
Are most of our lipids Exogenous or Endogenous?
Endogenous
What is the definition of Atherosclerosis?
Atherosclerosis is an inflammatory fibro-proliferative disorder
What are the stages of Atherosclerosis?
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
How is the Endothelium dysfunctional in Atherosclerosis?
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
What is Fatty Streak formation?
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)
What is a Complicated atherosclerotic plaque?
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
Why is the Fibrous cap important?
It separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors
What is the difference between a stable and unstable atherosclerotic plaque?
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
What is an unstable atherosclerotic plaque?
The cap of the complicated plaque ruptures and exposes the thrombogenic lipid core to circulating platelets and coagulation factors leading to thrombosis
Apart from thrombosis, what else can a complicated atherosclerotic plaque lead to?
The plaque can erode the artery wall, hardening it.
This results in thinning of the vessel wall, leading to aneurysm and possible haemorrhage
What do complicated lesions often contain?
Why is this relevant?
Calcium - causes hardening
Can be detected on a CT of the heart
Generally believed, the more calcium, the more symptomatic
What may lead to rupture of the fibrous cap?
Associated with greater influx and activation of macrophages, accompanied by the release of matrix metalloproteinases that are involved in the breakdown of collagen
What is the ‘good’ type of cholesterol?
What affects the ratio?
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
What is the difference between Small dense LDLs and modified LDLs?
Modified cause more atherosclerosis than small LDLs
They can get through the endothelium more easily
(Small dense LDLs are easily oxidised into modified LDLs)
What is considered a very high concentration of Triglycerides?
What risk is this associated with?
>1000mg/dL
Very high risk of Pancreatitis
(>200mg/dL is considered high)
What is the first-line treatment for Dyslipidaemia?
Statins - Highly effective in lowering LDLs and have a good tolerability profile
Where do Statins act?
On the Mevalonate pathway of Cholesterol Synthesis
They inhibit HMG-CoA Reductase - preventing Mevalonic acid from being produced
What are two important products produced during Cholesterol synthesis, and why?
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
How do Statins reduce elevated LDLs?
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
Name 5 major Statins
Which two have considerably longer half-lives?
Simvastatin (1-2h)
Fluvastatin (1-2h)
Pravastatin (1-2h)
Atorvastatin (14h)
Rosuvatatin (20h)
What is the rule of 6 with regards to Statins?
If you double the dose of any statin, you only get a 6% reduction in LDL cholesterol
What are the main side-effects of Statins?
GI Symptoms
Rashes
Myalgia
Rhabdomyolysis
Hepatotoxic - especially in those with preexisting liver disease
Teratogenic - avoid in pregnancy
What drugs other than Statins may be used to treat Dyslipidaemia?
Fibrates
Nicotinic acid
Ezetimibe
What are Fibrates?
What is their target?
What effect do they have?
What are they often used to treat?
They activate PPAR-alpha receptors
Lower plasma fatty acids and triglycerides (better than statins)
Often given to diabetics with high triglycerides
What is Ezetimibe?
What do they do?
Why may they be given?
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
