092914 pharm lipid disorders Flashcards
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)
adverse effects of niacin
skin flushing, pruritis–mediated by vasodilatory prostaglandins (can use NSAIDs to block effect). tolerance to flushing occurs with continued use
less frequent:
GI
elevated liver enzymes-no liver toxicity BUT MAJOR CONCERN if combined w statins
hyperuricemia (contradindicated for gout)
increases fasting glucose levels
drug interaction of niacin
combined use with statin increases risk of myopathy
niacin effect on lipoprotein profile
decreases TG
decreases LDL
increases HDL
decreases Lp(a)
uses of niacin
hypercholesterolemia, hypertriglyceridemia
typically not first line therapy for hypercholesterolemia (side effects)
ONLY lipid lowering drug that decreases Lp (a)
ezetimibe MOA
binds to NPC1L1 and inhibits cholesterol absorption by enterocyte. lowered cholesterol causes increase in LDL receptor expression.
cholesterol absorption inhibitor
side effects of ezetimibe
well tolerated
side effects increase if combined with other drugs like statins
ezetimibe effect on lipoprotein profile
decreases TG 5%
decreases LDL
increases HDL 1-2%
uses of ezetimibe
primary hypercholesterolemia
combined with statins (efficacy questioned)
fibric acid/fibrate/PPAR activators
gemfibrozil, fenofibrate
primarily lower TG-rich lipoproteins
MOA of fibrates
bind to PPARalpha (expressed primarily in liver and brown adipose tissue). PPAR binds with retinoid X receptor to form heterodimer. they bind to specific genetic response elements. effect is to reduce TGs, increase reverse cholesterol transport
what is an ex of a gene regulated by PPARalpha
lipoprotein lipase
adverse effects of fibrates
generally well tolerated
GI symptoms-most common
increased risk of gallstones
less common-hematological or hepatic abnormalities
if also using statin, increases creatine kinase, leading to renal failure
gemfibrozil side effect
can increase systemic statin concentrations by blocking tansporter in liver
fibrates are contraindicated in which pts
renal impairment pts
fibrates’ effect on lipoprotein profile
decreases TG
decreases LDL (highly variable)
increases HDL
uses of fibrates
pts with high TGs and low HDL associated with metabolic syndrome or type 2 diabetes
drugs of choice for hypercholesterolemia
statins-lifetime tx
bile acid resins (long term safety, younger pt, add on to statins)
ezetimibe (safety as monotherapy vs maybe add on to statins)
niacin (both elevated TG and cholesterol, low HDL)
drugs of choice for hypertriglyceridemia
gemfibrozil/fenofibrate-1st choice
niacin
omega 3 fatty acids
which drug has greatest effect at raising HDL?
niacin
side effect comparisons of drugs
see slide 90 and 91
effects of omega 3s
reduces rate of secretion of VLDL
reduce arrhythmia risk
stabilizes plaques
reduces HR
improves endothelial fxn
side effects of omega 3s
fish allergy
may increase LDL
may increase liver enzymes
may prolong bleeding time
use of omega 3s
adjunct in tx of hyperTG
PCSK9 inhibitors
antibodies that prevent PCSK9 binding to LDLR-LDL complex
MTP
microsomal triglyceride transfer protein–if you inhibit, prevents assembly of apo-B containing lipoproteins in enterocytes and hepatocytes, reducing chylomicrons, VLDL, LDL-C
side effects of MTP inhibitors
GI
hepatotoxicity
uses of MTP inhibitors
pts with homozygous familial hypercholesterolemia
apoB-100 inhibitor MOA
antisense oligonucleotide hybridizes with coding region of apoB-100 mRNA. activates RNaseH
side effects of apo-B inhibitors
injection site rxns
flu like symptoms
headache
elevation of liver enzymes
use of apo-B inhibitors
homozygous familial hypercholesterolemia
adjunct ot dietary therapy and other lipid lowering treatments
