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77 Cards in this Set
- Front
- Back
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what are the pathological hallmarks of atherosclerosis? |
focal lesions (fatty streaks) in the inner lining of arteries |
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what is one of the first signs of coronary artery disease & underlying atherosclerosis? |
angina |
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How can atherosclerosis be prevented |
reduce LDL (diet) increase HDL (exercise) quit smoking get rid of obesity, lower hypertension, erradicate diabetes. Decrease CRP Decrease coagulation factors (anti-thrombotics, antioxidants- vit C & E) improve endothelial fxn (ACE inhibitors--> inc NO) |
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what are the five major classes of lipoproteins?
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chylomicrons |
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Via the exogenous (intestinal) pathway- Dietary fats are absorbed by what organ? what are they repackaged as? |
small intestine, repackaged as chylomicrons with an apoliprotein B-48 |
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which apolipoproteins are given to chylomicrons by HDL in the blood stream? |
apoE and apoC |
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what is the function of Apo C?
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promotes the interactions of chylomicrons with Lipoprotein lipase (LPL) which will hydrolyze the Triglycerides into Free fatty acids. |
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where is lipoprotein lipase located? |
on the endothelial surface of adipose and muscle tissue (thus the hydrolyzed FFA can be stored at these locations as adipose tissue) |
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which apoprotein mediates the removal of chylomicron remnants (after hydrolyzation) from the circulation and into the liver?
(THIS is the end of the exogenous pathway) |
apoE |
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Endogenous pathway: What does the liver package cholesterol and triglycerides into? which apo protein accompanies it?
(This occurs when the exogenous path (diet) does not meet the fat energy needs) |
VLDL with apo B-100
(VLDL is high TG & low cholesterol) |
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Once VLDL in the liver gets released into circulation, what does it interact with?
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HDL- gives VLDL Apo C, Apo E, & choleteryl ester (via CETP) in exchange for some of its TGs
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what catabolizes VLDL in the endogenous (hepatic) pathway? what else is catabolized by this? |
LPL (lipoprotein lipase) - chylomicrons |
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After VLDL hydrolysis via LPL, what remains? |
IDL remnants & apoE (FFA have been released) |
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what percentage of VLDL remnants (IDL) are cleared by the liver by hepatic (ApoE) receptors?
what happens to the remaining portion? (all of these in the hepatic pathway) |
50%; the rest is further catabolized by LPL & hepatic lipase --> additional TGs removed & -->apoE and apoC form LDL particles. |
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how does plasma clearance of the LDL occur in the endogenous (hepatic) pathway? |
via LDL receptor mediated endocytosis--> LDL taken into liver & peripheral cells
**directed by LDL apo B-100
(LDL receptor expression is directly related to the amount of intracellular cholesterol, if already high cholesterol, more LDL will remain in plasma) |
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what are the four processes that maintain a tight control over the intracellular cholesterol levels? |
de novo synthesis, cellular uptake, storage efflux from the cell. |
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what is the rate limiting step in cholesterol biosynthesis? |
HMGCoA reductase |
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what happens when intracellular cholesterol is low? |
the transcription factor sterol regulatory element binding protein (SREBP) is released from the endoplasmic reticulum--> increase the expression of HMGCoA reductase & LDL receptors--> stimulates an uptake of cholesterol from bloodstream |
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What happens if the intracellular cholesterol is too high (excess)? |
-peripheral cells synthesize transporters for cholesterol efflux--> -cholesterol is released to ApoA1 in the circulation--> -immature HDL is formed--> -circulating HDL acquires free cholesterol--> -free cholesterol becomes cholesterol ester (via LCAT)--> -cholesterol ester is exchanged with an Apo B lipoprotein (to go back to liver)--> -HDL also transports cholesterol to liver & hormone producing tissues (via SR-BI)
(SREB--> HMGCoA & LDL receptors are downregulated-DUH) |
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In general, the intracellular cholesterol is inversely related to the ____________ |
LDL receptors & plasma LDL uptake
(high cell LDL--> low receptors & uptake--> high circulationg LDL) |
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Circulating LDL is the mechanism for ......
HDL is the mechanism for....... |
LDL: delivery of cholesterol (necessary for fxn) to peripheral cells BUT also delivers cholesterol to astherosclerotic lesions (macrophage foam cells) HDL: removes cholesterol from all ^ locations & returns it to the liver (as esterfied cholesterol) |
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what are the four categories of drugs that are anti-hyperlipdemics? |
statins, fibrates, cholesterol absorption inhibitors, niacin (nicotinic acid) |
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For high atherosclerotic risk, which lipoproteins are elevated? moderate risk?
What do you give these patients?
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high risk= LDL or VLDL (type II hyperlipidemia) tx: statins, if both ^ also give nicotinic acid, & fibrates
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If a pt presents with CHD, is a smoker, obese and has hypertension, what should the LDL goal be? |
<60 |
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if a pt presents with known CHD what should the LDL goal be?
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<100 |
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if a pt presents with obesity and diabetes, what should the LDL goal be?
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<130 |
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if a pt presents with absolutely no problems, what should the LDL goal be? |
<160 |
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what are the 4 pt groups who should be given statins?
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1. pt w/ clinical atherosclerotic cardiovascular disease/ ASCVD (CAD, MI, etc) 2. pt wl LDL > 190 mg/dL 3. pt w diabetes, age 40-75, & LDL > 70 mg/dL 4. pt 40-75 yr, LDL > 70, & ASCVD 10 yr risk > 7.5 %
(ASCVD risk based on equation using risk factor, race, gender, etc) |
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what is the MOA of statins?
site of action? |
inhibiting HMGCoA reductase. --> dec endogenous production of cholesterol --> dec plasma LDL --> Inc LDL receptor production --> inc LDL uptake & dec VLDL secretion. --> further dec LDL
IN LIVER* (statins are taken orally & metabolized in liver) |
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What else do statins do besides lowering LDL? |
-improve enodthelial fxn by increasing NO synthesis -stabilize plaque -anti-inflammatory by decr C-reactive protein (CRP) -reduce LDL oxidation -reduce platelet aggregation -reduce plasma TGs (a little bit) -increase HDL cholesterol |
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what are the side effects of statins? |
myalgia, GI, insomnia, rash and increase in liver enzymes.
Rare serious side effect: hepatotoxicity and myopathy (rhabdomylosis)
(pravastatin is most likely to cause myopathy. lovastatin & simvastatin are least likely) |
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what tests should you monitor if your pt is on a statin? |
ALT (hepatotoxicity) and CK/CPK (myopathy) |
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what are the contraindications for statins? |
pregnancy/ nursing-- teratogenic effects
CYP3A4 inhibitors (especially simvastin & lovastatin)--toxicity |
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why is statin a problem for drug interactions?
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because 90% are bound in plasma which allows them to react with other drugs.- high toxicity |
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what are the two subgroups of statins? |
specific competitive inhibitors and long lasting inhibitors |
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what are the five specific competitive inhibitors that are statins? |
fluvastatin lovastatin simvastin pravastatin pitavastin |
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which specific competitive inhibitor is the best at increasing the HDL level?
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fluvastatin
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which two specific competitive inhibitors are prodrugs? |
lovastatin and simvastin
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which specific competitive inhibitor can penetrate the CNS? |
simvastin (pro-drugs) |
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which group of statins are short acting and must be taken at night (when peak cholesterol synthesis occurs)? |
specific competitive inhibitors
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which statin has been proven to increase survival rate in CHD pts?
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simvastin
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what are the two members of the long lasting inhibitor statins? |
atorvastatin and rosuvastatin
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Which statins are the BEST at lowering LDL levels? |
the long lasting inhibitors -- atorvastatin & rosuvastatin |
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T/F Statins can be combined w/ bile acid squestrants, niacin, or fibrates to further reduce LDL |
TRUE
(combo w/ bile acid sequestrants is least likely to inc side effects) |
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when are fibrates the drug of choice?
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type 3 hypertriglyceridemia (high VLDLs)
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what is the MOA of fibrates
(site of action) |
-PPARalpha (peroxisome-proliferator associated receptor) agonists--> stimulates LPL on vascular endothelium--> increase catabolism of VLDL -decreased release of VLDL by liver--> decreased TGs -increased LDL liver uptake (dec plasma LDL) -increase Apo AI & AII--> Increase plasma HDL levels
(acts on vascular endothelium & liver) |
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what pts should you hesitate to give fibrates? which tests should be monitored? |
renal impairment --> fibrates undergo glucuronidation & are renally excreted
serum creatinine
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what are the SE of fibrates?
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Common SE: GI sx, pruritis, rash,
Severe SE: myositis (myoglobinura, rhabdomyolysis, acute renal failure) lithiasis (... more SE than statins) |
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what are the five fibrates? |
benafibrate, ciprofibrates, clofibrate, fenofibrate, gemfibrozil
(most common= bold) |
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which fibrate SIGNIFICANTLY causes lithiasis? ***** |
Clofibrate |
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which fibrate do you use in pts whose gallbladder has been removed? |
clofibrate |
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which fibrate crosses the placenta & goes into breast milk?
NEVER GIVE TO PREGNANT/NURSING |
gemofibrozil |
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why shouldn't you give fibrates to a patient who is on repaglinide? |
SEVERE hypoglycemia |
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what are the two categories of drugs that inhibitor cholesterol absorption and reabsorption in GI tract? |
Bile acid sequestrants (Coles-) and cholesterol transporter blocker (Ezitemibe-Zetia) |
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If a patient w/ statin managed hyperlipidemia begins to have an increase in LDL (resistance), what should you add for adjunct tx? |
a bile acid sequestrant (keep on statin) |
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what drugs are bile acid sequestrants? |
colestyramine, colestipol, colesevelam |
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what is the MOA of Bile acid sequestrants? |
Increased excretion of bile acids into feces--> liver makes more bile using intracellular cholesterol--> (this causes transient TG inc) dec intracellular LDL--> Increase LDL receptor expression---> increased clearance of LDL from plasma--> dec plasma LDL |
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In addition to lowering LDL, bile acid sequestrants also reduce the risk of what? |
CHD & MI |
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what are the side effects of bile acid sequestrants? |
- GI: bloating, dyspepsia
- dec absorption of fat soluble drugs
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what drugs are made less effective bile acid sequestrants? |
interfere w/ absorption of fat soluble drugs: (take bile acid sequestrant 4-6 hrs before or after these drugs to decr this effect) |
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what drugs are cholesterol transporter blockers? |
ezitemibe (Zetia) vytorin niacin (nicotinamide) |
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what drug is an adjunct to diet and statin that does NOT cause dec absorption of fat soluble vitamins & drugs? |
ezitemibe |
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what is the MOA of ezitemibe? |
specifically inhibits absorption of chol from duodenum by blocking cholesterol transport (NPCILI)--> Dec exogenous cholesterol--> dec plasma LDL
(taken orally & acts on intestinal epithelial cells at brush border) |
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what are the side effects of ezitemibe? |
diarrhea, abdominal pain, headache, rash, angioedema
(generally well-tolerated, use instead of bile sequestrants) |
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who cannot be on ezitemibe? |
someone breast feeding
(enters milk) |
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T/F
ezitemibe has a very short half life. |
FALSE
long 1/2 life: 22 hours |
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what can you do to sequester more bile acids without drugs? |
eat more fiber |
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what is vytorin? |
combo of ezetimibe & simvastatin |
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(Vytorin) ezetimibe + simvastatin leads to what type of reduction? |
60% reduction in LDL-C
(controversial, whether or not it is any more effective at reducing plaque, also very expensive) |
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what drug is the best agent available agent for increase HDL (30-40%)? what is the only thing better? |
Niacin (nicotinic acid) (add on to statin, also reduces risk of MI)
exercise
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what enzyme is inhibited by niacin? |
Hormone sensitive lipase (HSL) to decrease formation and transport of FFA into liver--> thus dec TGs--> dec VLDL, HDL, LDL |
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what are the SE of niacin? |
flushing & pruritus, (due to PGD, aspirin dec this effect) palpitations GI -dyspepsia.
At high does: hepatotoxicity (elevates ALT & AST) impaired glucose tolerance precipitates gout by increasing urate |
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who is niacin contraindicated for? |
diabetes pregnant people
(gout, liver issues) |
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how long does it take to see the affects of niacin?
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3-6 weeks
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What can be used as an adjunct for high TG? |
omega-3-acid ethyl esters (Lovaza) |
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Why is familial hypercholesterolemia difficult to treat w/ statins, etc?
What can be added to help decrease LDL? |
lack LDL receptors
add; -LDL diuresis -lomitapide (inhibits MTP synth of Apo-B) -mipomersen (inhibits oligonucleotide synth of Apo B-100) |
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Why are lomitapide & mipomerson not recommended for normal dyslipidemia? |
SEVERE hepatotoxicity
also contraindicated in pregnancy |
