Atherosclerosis & Lipid-lowering Drugs Flashcards
What defines if something is HDL or LDL?
APOPROTEINS
• A-1 = HDL
• B = LDL
Explain the exogenous pathways of lipid metabolism
When we eat food:
- It is broken down into chylomicrons (large)
- These are further broken down into FFAs + chylomicron remnants
- Chylomicron remnants –> deposit in vessels –> atheroma
Explain the endogenous pathways
MOST HDL/LDL comes from this pathway
• Lipoprotein lipase & Hepatic lipase metabolise the most
• IDL & LDLS are deposited in vessels to form atheromas
Explain what is meant by ‘Reverse Cholesterol Transport’
The REMOVAL of cholesterol from VESSEL WALLS
back to the liver by HDL!
Define atherosclerosis
An inflammatory fibro-proliferative disorder
Remnant cholesterol is PRO-inflammatory
8 general steps that leads to atherosclerosis?
- LDL enters endothelium (into tunica intima (media is VSMCs))
- LDLs are oxidised by macrophages and VSMCs
- Release of growth factors and cytokines
- Additional monocytes/macrophages recruited
- Foam cell accumulation (macrophages that contain lots of lipids)
- VSMC migration
- VSMC proliferation
- Plaque growth
Explain the ‘Endothelial Dysfunction’ part of Atherosclerosis
It is characterised by: Increased endothelial permeability Upregulation of adhesion molecules Leucocyte adhesion Migration of leucocytes into artery wall
Explain the ‘Fatty Streak Formation’ of Atherosclerosis
The earliest recognisable lesion of atherosclerosis
• caused my FOAM CELL aggregation
- derived from macrophages & T-cells within the tunica intima
• fatty streaks usually form in the DIRECTION of BLOOD FLOW
It is characterised by: Migration of VSMCs (included later on) Activation of T-cells Adherence & activation of platelets Formation of foam cells
Explain the ‘Plaque Formation’ of Atherosclerosis
It is characterised by:
Formation of fibrous cap
- VSMCs migrate to intima & lay-down collagen fibres
- separates the lipid-rich core from circulating platelets * coagulation factors
Accumulation of macrophages
Formation of necrotic core
- in STABLE atherosclerotic plaques
Foam cells die & rupture
What are the different types of Atherosclerotic lesions?
1. Lesion-prone location – Adaptive thickening. 2. Type 2 lesion – foam cells. 3. Type 3 lesion (preatheroma) – extracellular lipid. 4. Type 4 lesion (atheroma) – bigger core of extracellular lipid. 5. Type 5 lesion (fibroatheroma) – fibrous thickening. 6. Type 6 lesion (complicated lesion) – fissure & haematoma.
(onenote!!)
What effect does remnant lipids have on the endothelium
The remnant lipids are the CHYLOMICRON remnants that are very good at infiltrating the endothelial wall
Remnants include:
• VLDL
• Chylomicron remnants
• IDL
Note – remnants are MORE important than LDLs here!
What causes the INFLAMMATORY part of atherosclerosis?
Lipid remnants!
NOT LDL
Charactertics of a STABLE vs. UNSTABLE plaque?
Stable plaque
– thick fibrous cap
– sometimes have a thinner lumen but are less likely to rupture
Unstable plaque
– thin fibrous cap
– rich core of lipids & macrophages
– less evidence of VSMC proliferation
What normally happens if the atherosclerotic plaque is unstable?
Plaque
• ruptures
&
• exposes the thrombogenic lipid-rich core to circulating platelets & coagulation factors
Leads to THROMBOSIS
Note: the cell in the plaque also produces loads of factors that promotes inflammation & cause other cells to be attracted to the lesion causing:
• cells to proliferate
• plaque erosion
LDL vs. HDL?
LDL
– strongly associated with atherosclerosis & CHD events
– 10% increase LDL –> 20% increase in CHD events
o These events are modified by – smoking, low HDL, hypertension & diabetes
HDL
– protective effect for atherosclerosis & CHD events
o HDL tends to be low when TG are high
o HDL is lowered by – smoking, obesity, physical inactivity
Drug therapies for Atherosclerosis?
Statins
• 1st line treatment for dyslipidaemia (effective at lowering LDL)
• good compliance
Bile Acid Sequestrants
• poor compliance (due to side-effects)
Nicotinic Acid
• effective at increasing HDL
• BUT has various SEs
Fibrates
Probucol
Explain the MoA of statins
HMG-CoA Reductase inhibitors
(works on mevalonate pathways)
o This halts the cholesterol synthesis pathway.
o Halts specifically the rate-limiting step.
o Reduces the modification of proteins involved in modifying gene translation to create LDL
This has the effect of UP-REGULATING the LDL receptors expressed on hepatocytes in the liver which results in more LDL being removed from the blood
This also results in more HDL levels in the blood
What else does Statin block?
Geranyl & Farnesyl pyrophosphate
(mevalonate pathway)
• small lipids
• important in cells as involved in modification & activation of proteins (Rho, Ras)
Cells can NOT function properly without these lipids
What 2 things determines the different Statins properties?
Selectivity ratio
– the HIGHER the selectivity ratio, the GREATER the chance of it being concentrated in the HEPATOCYTE
o I.E. Simvastatin gets into many cells as it’s very lipid soluble. Pravastatin is mainly hepatocytes
Potency
– the LOWER the number, the MORE POWERFUL the drug is as an inhibitor of the enzyme
Which statin has the greatest effect?
Rosuvastatin
• BUT only has a modest effect in reducing TG
What is the ‘Rule of 6’?
Doubling the dose (of statins) ONLY makes a 6% extra reduction
Note: ONLY with statins
Explain the Statin Trials and the Spectrum of Risk
Different trials were designed to measure the effect of statins on different CHD risk groups of patients from low-risk –> high-risk
o 4S1 trial – CHD/high cholesterol group
o WOSCOPS6 – No MI/high cholesterol
Results showed that irrespective of risk group, all patients benefitted from a 30% reduction in risk
Lowered LDLs too much resulted in problems in the CNS and memory
What is the general summary of statins use?
Statins can be described to have a PLEIOTROPIC effect
– both good and bad effects
Statins have multiple effects not directly related to lowering cholesterol (e.g. anti-inflammatory action)
MoA of fibrates?
MoA – PPAR-alpha receptor agonist
– PPAR – Peroxisome Proliferator Activated Receptors
– Act on the liver
Decrease FFAs and TGs.
Increases HDL very effectively but LDL doesn’t change a lot
