Pharm 17: Atherosclerosis + Lipo-metabolism Flashcards
Describe the structure of lipoprotein
LDLs
HDLs
LDLs –> Cholesterol esters + TGs in core, surrounded by phospholipid monolayer with apoprotein B
o HDLs –> have apoprotein A-1 on surface
Describe the exogenous pathway of Lipid metabolism
absorption of fat from diet
- dietary TG + cholesterol = taken up in the intestines
- broken due to CM
- LP lipase converts CM to CM remnants –> which can form atheroma
Describe the endogenous pathway of Lipid metabolism
liver
- generates lipids which are
broken down converted –> binds to LDL receptor
describe what is Reverse CL transport
when cholesterol = taken out of blood vessel’s foam cells
- transformation of HDL –> LDL
you can
- block this process –>by blocking cholesterol ester transfer protein –> so you get more HDL, less LDL
how does endothelial dysfunction occur in atherosclerosis ?
there is:
Increased endothelial permeability –> causes upregulation of endothelial adhesion molecules –> increased leukocyte adhesion –> migration of leukocytes into arterial wall
how does fatty streak formation occur in atherosclerosis ?
Caused by aggregation of lipid-rich foam cells (from macrophages + T cells) in tunica intima (inner most part of arterial wall)
o Fatty streaks are common; may increase in size, remain static or disappear
Describe the formation of complicated atherosclerotic plaque in advance stage in atherosclerosis
1) Formed by death + rupture of lipid-laden foam cells in fatty streak.
2) Migration of VSMCs to intima + laying down of collagen fibres –> forms protective fibrous cap over lipid core.
3) Fibrous cap (mostly collagen) crucial in mature atherosclerotic plaque b/c it separates highly thrombogenic lipid-rich core from circulating platelets and other CFs.
4) Stable plaques have necrotic lipid core covered by thick VSM-rich fibrous cap.
5) Lesions expand at shoulders by continued leukocyte adhesion.
why are remnant lipids bad
- Remnant lipoprotein from CM breakdown are atherogenic –> higher CHD risk
- Remnants (VLDL, CM remnant, IDL) get modified in intima + affect macrophages
what are vulnerable atherosclerotic plaques ?
- Thin fibrous cap, lipid/macrophage-rich core, little SM proliferation –> may break if high surge in BP; prone to rupture + ulceration –> rapid development of thrombi.
- Rupture = associated with greater influx + activation of macrophages, accompanied by release of matrix metalloproteinases involved with collagen breakdown
whats the difference between LDL vs HDL ?
LDL:
- strong association with CHD events
- 10% increase in LDL = 20% increase in CHD risk
HDL:
- has protective effect
- promotes reverse cholesterol transport
- low HDL –> high CHD risk
- HDL = low, when Triglyceride = high
- HDL –> lowered by smoking/obesity
what are the general mechanisms of lipid lowering therapies
a) HMG COA reductase inhibitor (statins)
b) Bile acid sequestrants
c) nicotinic acid
d) fibrates
e) probucol
what are the general mechanisms of lipid lowering therapies
a) HMG COA reductase inhibitor (statins)
- -> lowers LDL
b) Bile acid sequestrants
- -> potent cholesterol-lowering agents.
c) nicotinic acid
- -> B-complex vitamin with lipid-lowering properties
- -> decrease platelet aggregation
- -> increases HDL
d) fibrates
- ->triglyceride-lowering drugs
e) probucol
- -> modest LDL cholesterol-lowering effect
describe the mechanism of action of statins
HMG Coa reductase inhibitors
- prevent HMG CoA conversion into cholesterol
- reduce amount of cholesterol synthesis in hepatocyte
–> which responds to this by expressing more LDL receptors on its surface
–> increase in LDL uptake –> reduces LDL levels in blood
then LDL = broken down in liver
Note: by inhibiting HMG CoA –> you starve hepatocyte of cholesterol –> so it tries to get it from the blood
how do fibrates work as lipid lowering therapy
activates of PPAR alpha receptors
PPAR = peroxisome proliferator activated receptors
- -> lower plasma FFAs + TGs by increasing cellular uptake + metabolism;
- -> increase HDL-CL
- -> reduce inflammation
other effects:
o Lower thrombosis/improve plaque stability
o Decrease cell recruitment/activation (e.g. less MCP-1)
o Lower vasoconstriction/cell migration
o Increase CL efflux + Decrease foam cell formation
describe the mechanism of action of nicotinic acid as a lipid lowering therapy
- Decrease TC/LDL/TG, increase HDL, and decrease CRP/fibrinogen
–> clots dissolved quicker, but poorly-tolerated due to e.g. intense flushing; also, little benefit
describe the mechanism of action of ezetimibe acid as a lipid lowering therapy
- Inhibits CL absorption
- Mechanism: absorbed then activated as glucuronide
- Can give ezetimibe alongside statins –> larger decrease in LDL than if just keep doubling statin dose significantly
(helps with rule of 6)
