Atherosclerosis and lipid lowering drugs Flashcards
what do the apoproteins define?
the type of lipoprotein
A-1: HDL
B: LDL
describe the exogenous pathway of lipid metabolism
- when we eat food, it is broken down into chylomicrons (large)
- which are broken down into FFAs and chylomicron remnants
- remnants deposit in vessels
- atheroma
describe the endogenous pathway
- most LDL/HDL comes from this
- lipoprotein lipase and hepatic lipase metabolise most
- HDLs and LDLs are deposited in vessels to form atheromas
what is reverse cholesterol transport?
removal of cholesterol from vessel walls back to liver by HDL
define atherosclerosis
inflammatory fibro-proliferative disorder
describe the steps to atherosclerosis
- LDL enters endothelium into tunica intima
- LDLs are oxisided by macrophages and VSMCs
- release of GF and cytokines
- additional monocytes/macrophages recruited
- Foam cell accumulation
- VSMC migration
- VSMC proliferation
- plaque growth
what is in the tunica media?
VSMCs
describe the endothelial dysfunction in atherosclerosis
- inc. endothelial permeability
- upregulation of adhesion molecules
- leucocyte adhesion
- migration of leucocytes into artery wall
describe the fatty streak formation
- migration of VSMCs
- activation of T cells
- adherence and activation of platelets
- formation of foam cells
describe complicated plaque formation
- formation of fibrous cap
- accumulation of macrophages
- formation of necrotic core
describe what is seen in the different lesions in atherosclerosis
- lesion-prone location = adaptive thickening
- type 2 lesion = foam cells
- type 3 lesion (preatheroma) = extracellular lipid
- type 4 lesion (atheroma) = bigger core of extracellular lipid
- type 5 lesion (fibroatheroma) = fibrous thickening
- type 6 lesion (complicated lesion) = fissure and haematoma
what are the remnant lipids?
chylomicron remnants that are very good at infiltrating endothelial wall remnants include: - VLDL - CM remnants - IDL
what is the inflammatory part of atherosclerosis caused by?
lipid remnants
describe a stable plauque
- thick fibrous cap
- thinner lumen
- less likely to rupture
describe an unstable plaque
- thin fibrous cap
- rich core of lipids and macrophages
- less evidence of VSMC proliferation
what are LDLs associated with? what are these events modified by?
associated w/ atherosclerosis and CHD events
10% inc. in LDL –> 20% inc. in CHD events
events modified by: smoking, low HDL, hypertension, diabetes
what is HDL? what is HDL lowered by?
- protective effect for atherosclerosis and CHD events
- HDL tends to be low when TG are high
- HDL lowered by smoking, obesity, physical inactivity
what are the 3 different drug therapies used in the past?
- bile acid sequestrants - poor compliance
- nicotinic acid (inc. HDL well but SEs)
- statins (1st line treatment for dyslipidaemia, highly effective at lowering LDL)
what is the MoA of statins?
HMG-CoA reductase inhibitors
- halts cholesterol synthesis pathway at RLS
- reduces modification of proteins involved in modifying gene translation to create LDL
what effect do statins have on the LDL receptors?
- up regulate the LDL receptors expressed on hepatocytes in liver
- results in more LDL being removed from blood
- results in more HDL levels
what is the selectivity ratio?
- higher selectivity ratio, greater the chance of it being concentrated in hepatocyte
e.g. Simvastatin = 0.54, Pravastatin = 3.3
simvastatin gets into many cells as is very lipid soluble, pravastatin mainly hepatocytes
what is potency?
lower the number, the more powerful the drug is as an inhibitor of enzyme
which statin has the greatest effect in reducing LDL and raising HDL?
Rosuvastatin
but just has a modest effect in reducing TG
what is the rule of 6?
doubling the dose ONLY makes a 6% extra reduction
what happens when LDLs are lowered too much?
problems in CNS and memory
what is the MoA of fibrates?
PPAR-alpha receptor agonist
PPAR (peroxisome proliferator activated receptors)
act on liver
dec. FFAs and TGs
inc. HDL very well but LDL doesn’t change a lot
what does Ezetimibe do?
- inhibits cholesterol absorption
- ezetimibe –> glucuronide in intestines = ACTIVATED
what can Ezetimibe be coadministered with?
statins to avoid rule of 6
statins have more dramatic effect at lowering LDL
what do cholesterol ester transfer protein (CETP) inhibitors do?
- CETP converts HDL into LDL
- inhibiting it causes inc. HDL
- but their use lead to a lot of unexpected deaths so use discontinued
What is PCSK9?
- inhibitor of LDL receptor
- monoclonal anti-PCSK9 antibodies inactivate PCSK9 so more LDL can be absorbed by lower
- people with familial hypercholesterolemia benefit well
