092914 pharm lipid disorders Flashcards
(54 cards)
HMG CoA reductase inhibitors/statins. list them
atorvastatin
lovastatin
simvastatin
MOA of statins
competitive inhibitor for active site on HMG coA reductase (rate limiting step in cholesterol synthesis)
share structural component that is very similar to HMG portion of HMG-CoA
SREBP-what happens to it when sterols are low?
normally, SREBP is anchored in ER with SCAP and INSIG
if sterols are low, SCAP and INSIG no longer bind, so SREBP and SCAP move to the Golgi. SCAP is cleaved by site 1 protease and site 2 protease. now get a transcriptionally active SREBP that moves to nucleus to activate transcription of target genes. bind to sterol-responsive element of the LDL receptor gene
pharmacokinetics of statins
extensive first pass metabolism by liver–targets liver, the site of action
thereby prevents escape of drug molecules into circulating blood
which are the two statins that are inactive lactones and must be transformed inthe liver to hydroxy acids?
simvastatin, lovastatin
how are atorvastatin, lovastatin, simvastatin metablized?
CYP3A4
adverse effects of statins in percentage of population that develop them
10% of pts develop intolerant symptoms
1-2% develop serious side effects such as myositis or liver enzyme elevations
major adverse effects of statins
myopathy-muscle pain, weakness. no or little CK elevation
rhabdomyolysis-marked CK elevation. breakdown of muscle fibers that leads to release of myoglobin into bloodstream, causing kidney damage
myopathy risk factors (when treating with statins)
high statin dose
high plasma concentration
genetic variants of what can contribute to statin intolerance?
SLCO1B1, which encoes organic anion transporter that regulates hepatic uptake of statins. polymorphism of this is associated with statin induced myopathy
contraindications to statin therapy
hypersensitivity
active liver disease
PREGNANT WOMEN or women LACTATING, or likely to become pregnant
statin effect on lipoprotein profile
decreases triglycerides
decreases LDL
increases HDL
uses of statins
first line for hypercholesterolemia when at risk for MI
what is the only mechanism by which cholesterol is excreted?
conversion to bile salts
cholestyramine MOA
highly positively charged and binds negatively charged bile acids
b/c of its large size-the resins are not absorbed and the bound bile acids are excreted in the stool
by depleting pool of bild acids, hepatic bile acid synthesis increases (uses up more cholesterol, causing production of LDL receptors, a pathway similar to statins)
what is the dominant mechanism for controlling LDL plasma concentrations
regulation of hepatic LDL receptor pathway
how is cholestyramine administered?
as a hygroscopic powder administered with water
adverse effects of cholestyramine
most common-constipation, bloating
gritty consistency
interferes with absorption of other drugs (not absorbed itself)
modest INCREASE in TG, with time returns to baseline
cholestyramine effect on lipoprotein profile
if TG is normal, only transient increase
if TG is greater than 250 mg/dl, get INCREASE
decreases LDL
increases HDL
uses of cholestyramine
hypercholesterolemia
not recommended for people with hypercholes and increased TG
usually used as second agents if statin does not lower LDL choles enough
recommended for pts 11-20 yrs old
nicotinic acid is also called
niacin
niacin
water soluble B complex vitamin–prescription b/c used in much higher doses than vitamin
lipid lowering effect is unrelated to effect as vitamin
MAIN effect is to decrease TG (but does lower cholesterol)
MOA of niacin
MOA not well understood
in adipose tissue, inhibits free fatty acid mobilization
in liver, decreases VLDL triglyceride production and increases apoB degradation
inhibits uptake of HDL-apoA1 (apoA1 activates LCAT)
niacin has what effects
decreased serum VLDL
decreased serum LDL (but not through an increase of LDL receptor)
