Atherosclerosis Flashcards
What is the cholesterol biosynthetic pathway?
acetyl CoA–> HMG CoA–> mavalonic acid via HMG CoA reductase–> geranyl pyrophosphate–> farnesyl pyrophosphate–> cholesterol
What are triglycerides?
an ester; glycerol + 3 fatty acids; component of animal fat and vegetable oil; store and circulate fat; important source of energy
What are lipoproteins?
complex of lipids & proteins w/ hydrophobic core; enable transport of lipids (triglycerides to periphery)
exogenous pathway of lipid metabolism
intestinal absorption of dietary cholesterol & fatty acids; free fatty acids combine w/ glycerol to form triglycerides; cholesterol esterified to cholesterol esters via ACAT; triglycerides & cholesterol assembled into chylomicrons that enter circulation; lipoprotein lipase hydrolyzes (removes) triglycerides in extrahepatic tissues; chylomicron remnants taken up by hepatocytes
high density lipoproteins
HDL; small diameter; high density; B-100 apolipoproteins
low density lipoproteins
LDL; larger diameter; less dense; B-100 apolipoproteins
very low density lipoproteins
VLDL; large diameter; low density; B-100 apolipoproteins
chylomicrons
largest diameter; low density; B-48 apolipoproteins
endogenous pathway of lipid metabolism
nutrient deficiency; liver packages triglycerides into VLDL; muscle or adipose pick up free fatty acids; remnants (IDL) rich in cholesterol esters can go back to liver for metabolism or have triglyceride further removed to be left w/ LDL; LDL is rich in esters so can be taken back to liver for metabolism or stripped of extra cholesterol & turned into HDL
mechanism of action of hypolipidemic agents
prevent intestinal absorption of cholesterol or bile acids; decrease cholesterol synthesis (increase LDL receptors & uptake); inhibit VLDL secretion (decrease LDL production); upregulate lipoprotein lipase (decrease triglycerides)
What is CYP7A1?
rate-limiting enzyme of converting cholesterol into bile acids
What is the negative feedback loop of cholesterol use in the body?
bile acids activate nuclear hormone receptor FXR in ileocyte; hormone FGF-15/19 goes back to liver via portal circulation to regulate expression of CYP7A1; regulates amt of bile acids generated; prevents body from using too much cholesterol
mechanism of action of bile acid sequestrants
target the negative feedback loop; prevent reabsorption of bile acids; bile acids needed to burn up cholesterol
mechanism of action of nicotinic acid
impairs production of VLDL to decrease LDL production; decreases triglycerides
mechanism of action of HMG CoA reductase inhibitors
competitive inhibition; liver senses low cholesterol levels; decrease cholesterol synthesis & upregulate LDL receptors on hepatocytes (decrease circulating LDL)
Why do statins need to be taken in the evening?
They are HMG CoA reductase inhibitors. Cholesterol synthesis takes place at night.
drug-drug interactions of CYP3A4 substrate statins
increased drug levels in CYP3A4 inhibitors (fibrates, macrolides, cyclosporine); decreased drug levels in CYP3A4 inducers (phenytoin, barbs)
drug-drug interactions of CYP2C9 substrate statins
increased drug levels in CYP2C9 inhibitors (azoles, amiodarone)
Which medications are affected by grapefruit juice?
lovastatin, simvastatin, atorvastatin; juice inhibits CYP3A4
mechanism of action of fibric acids
ligands for PPAR alpha; upregulate lipoprotein lipase, apo A-I, apo A-II; clears chylomicrons and VLDL; lowers VLDL & raises HDL
mechanism of action of exetimibe
impairs intestinal absorption of cholesterol; absorbed & glucuronidated; excreted into bile & feces
