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89 Cards in this Set
- Front
- Back
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What lipoproteins have high TG's?
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chylomicrons and VLDL
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What lipoprotein has the most protein content (opposed to lipid)
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HDL
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What does the LCAT do?
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It esterifies the cholesterol in HDL so HDL becomes spherical
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What is the apoprotein for chylomicrons?
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apo B48
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What is the apoprotein for VLDL?
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apo B100
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VLDL carries ?
LDL carries ? |
VLDL- TG's; LDL- cholesterol esters
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What is the MOA of lovastatin?
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competitively inhibits HMG-Coa Reductase
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LPL (lipoprotein lipase) is on the surface of the endothelium of capillaries in what parts of the body?
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capillaries of adipose tissue, skeletal muscle, and smooth muscle
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In what tissues is Km of LPL high? Low?
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high in adipose tissue, low in cardiac and skeletal muscle
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Where is the apo B100 made?
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Liver
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In the blood, what are FA's bound to (when not free)?
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albumin
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What is the common intermediate of triacylglycerol formation in adipose tissue and the liver?
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phosphatidic acid
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A critical functional protein, MTP, is missing in what disease? (the result is inability for form VLDL and chylomicrons)
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Abetalipoproteinemia
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Exogenous trigylcerides are carried by what? Endogenous?
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Exo: chylomicrons; Endo: VLDL
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What apoprotein activates LPL?
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CII
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What apoprotein acts as a ligand and helps chylomicron remnants get taken up by the liver?
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apoE
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What apoproteins are associated with HDL?
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A (I & II) and carries CII and E to other lipoproteins
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What is the function of CETP?
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An enzyme found in HDL. It transfers cholesterol ester from HDL to VLDL and takes TG from VLDL converting it to LDL
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What is defective in familial hypercholesterolemia?
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LDL receptor
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What is wrong in type II hyperlipidemia?
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Lack of functional LDL receptors
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What is wrong in cholesterol ester storage disease?
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Decreased activity of lysosomal esterase (acid lipase)
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What goes wrong in Wolman’s Disease
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Absence of lysosomal esterase
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Characteristics of Alpha-lipoprotein deficiency?
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– Decreased HDL
– VLDL and LDL may be decreased – Deposition of cholesterol esters in RES – Defective ABC1 |
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Characteristics of Lecithin-Cholesterol Acyltransferase Deficiency?
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– Decreased esterification of cholesterol
– Decreased LDL and HDL – Increased VLDL and chylomicrons – Foam cells in bone marrow and kidneys |
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Big one. What are the characteristics of the types of hyperlipoproteinemias?
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– Type I = Presence of chylomicrons (Increased
triglyceride) – Type IIa = Increased LDL (Increased cholesterol) – Type IIb = Increased LDL and VLDL (Increased cholesterol and triglyceride) – Type III = Increased IDL (Increased cholesterol and triglyceride) – Type IV = Increased VLDL (Increased triglyceride) – Type V = Increased VLDL and presence of chylomicrons (Increased triglyceride) |
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What is the primary means of clearance of HDL from the blood?
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Uptake by the liver and other tissues via scavenger receptor SR-B1
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What are the major lipids bound to HDL?
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phospholipids and cholesterol
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Which serum lipoprotein is found in the highest concentration?
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Avg conc. in mg/dl: LDL> HDL> VLDL> chylomicrons
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In general, what must be "taken" from VLDL in order for it to be converted to IDL?
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HDL must take both apoCII AND apoE
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What are three general outcomes of LDL binding and internalization in extrahepatic tissues?
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1. Dec. HMG CoA reductase
2. Increase in ACAT (esterifies intracellular cholesterol) 3.Downregulate LDL receptors |
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Which two HMG-CoA reductase inhibitors are administered as prodrugs?
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lovastatin and simvastatin
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What state/form of drugs is especially susceptible to drug-drug interactions?
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prodrugs
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True or False. The higher the anti-hyperlipidemic drug the greater the effect.
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False. Doesn't always correlate.
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What is the rate-limiting step in formation of cholesterol?
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HMG-CoA reductase
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True or False. If I raise the dose of Fluvastatin from 40 mg to 80 mg I can expect a proportional drop in cholesterol.
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FALSE... see slide titled "majority of LDL-C lowering occurs at the LOWEST-statin dose
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What are the two major AE's of pretty much all anti-hyperlipedemics?
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MUSCLE AND LIVER
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You put a pt. on Lovastatin. 2 weeks later they come in and say "i feel like i have the flu!". What lab should you (have been) monitoring?
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CK for myopathy! (An important AE is myopathy)
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Before you get into a "statin cocktail" with a patient what baseline labs should you probably order?
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AST/ALT, and CK
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What is the MOA of cholestryamine?
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non-absorbabale anion-exchange resins/polymers bind bile acids in intestinal lumen. this results in upregulation of LDL-C receptors and cholesterol 7-alpha hydroxlyase
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Hypercholesterol pt. has a major problem w/ low HDL and high TG. What drug do you NEVER choose as monotherapy in this case?
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Bile Acid sequestrants
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You're taking a med history of a pt. you saw a couple months ago. They say, "well i've been taking my colestipol, antacid, and my other meds in the morning w/ breakfast." What are they doing wrong?
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Don't take bile acid sequestrants or antacids w/ any other drugs!
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If you realllly need to raise HDL in your pt., (their level for HDL is 21) what is the target drug to add to the statin?
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Niacin (potent inc. in HDL)
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Pt. is taking 1000 mg of Niacin. What is the biggest AE? How can you prevent it?
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cutaneous flushing (cherry red); prevent by starting low (even though its ineffective at first) and take an ASA before taking niacin
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Pt. has gout or diabetes. What anti-hyperlipidemic do you avoid?
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niacin (elevates serum glucose and uric acid)
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Pt. primarily has hypertriglyceridemia problem. What is your DOC?
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Fibrates (PPAR-alpha activators)
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What is the MOA of Lovastatin?
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COMPETITIVELY inhibits HMG-CoA reductase (rate-limiting step in prod. of mevalonate and cholesterol)
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What are the effects of statins?
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1.up-regulation of LDL-C receptors
2. increase in lipid metabolism 3. reduce LDL-C (20-50%) 4. reduce TG (10-15%) 5. raise HDL (5-15%) |
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The majority of LDL-C lowering occurs at what statin dose?
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LOWEST statin dose
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2 contraindications for statin?
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pregnancy (category X)
acute/chronic liver and renal failure |
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What are the 3 bile acid sequestrants?
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Cholestryamine, colestipol, colesevalam (all chol/col)
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General effects of bile acid sequestrants?
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1. Reduce LDL-C (15-30%)
2. No effect on HDL 3. No chance to slight inc. in TG 4. upregulation of LDL-C receptors and cholesterol 7-alpha hydroxylase |
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Most common complaint of pt.s on bile acid sequestrants?
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bloating (big problem is vit. k absorption problems resulting in bleeding/hypoprothrombinemia
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What anti-hyperlipidemic acts locally?
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ezetimibe (cholesterol absorption inhibitors)
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If you were to give a bile acid sequestrant to a pregnant pt., which one is the best choice?
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colesevelam (preg. cat. B) b/c it acts locally
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What is a big contraindication of bile acid sequestrants?
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hypertriglyceridemia
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What is the believed MOA of Niacin?
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1. involved in reduction in cellular/enzymatic hepatic synthesis of TG, VLDL-C and LDL-C
2. increased LDL-C receptor activity 3. decreased HDL-C catabolism |
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What are the lipoprotein effects of niacin?
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1. reduce TG (20-50%)
2. reduce T-C (10-25%) 3. reduce LDL-C (5-25%) 4. INC. HDL (15-35%) |
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What are some contraindications of Niacin tx?
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chronic liver/gallbladder disease, severe GOUT, peptic ulcer disease, diabetes, bleeding disorders/thrombocytopenia (WARFARIN), pregnancy (C)
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What are the PPAR-alpha activators?
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gemfibrozil and fenofibrate (pro-drug)... the FIBRATES
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What is the MOA of gemfibrozil?
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activation of PPARs (transcription of gene involved in lipoprotein metabolism)
Results: 1. inc. catabolism of VLDL/IDL via LPL 2. dec. hepatic FFA extraction 3. inhibit hepatic acetyl CoA carboxylase 4. inc. HDL via inc. VLDL clearance |
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What are the lipoprotein effects of fibrates?
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What are 3 contraindications for fibrates?
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1. severe renal/hepatic disease
2. biliary cirrhosis 3. pregnancy (C) |
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What is the MOA of ezetimibe?
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selectively inhibits (at brush border of SI) absoprtion of cholesterol and phytosterols (reduces delivery of cholesterol to liver)
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What are the lipoprotein effects of cholesterol absorption inhibitors?
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ALL relatively small changes!
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What are the major AE's of ezetimibe?
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GI (diarrhea, abd pain, fatigue, back pain)
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What fish oil product is FDA-approved?
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lovaza
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Of the supplemental polyunsaturated fats, which are proinflammatory/thrombotic and which are anti-inflammatory/thrombotic?
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omega-6 are pro
omega-3 are anti |
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What are the 4 main components of fish oil?
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omega-3 FA's, EPA, DHA, & ALA
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Lipoprotein effects of fish oil?
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How do you monitor fish oil supplementation?
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liver enzymes and renal function (SCr/BUN)
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What are the highest risk factors for atheroslcerosis and CAD (i think)?
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2 non-alterable risk factors for CAD?
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heredity (male <55, female <65) and age (male >45, female >55)
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3 alterable risk factors for CAD?
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1. BP (>140/90)
2. smoking 3. HDL-C |
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Partial risk factors for CAD?
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TOE: tryglycerides, obesity, exercise (lack of)
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What pt.s shouldn't get ezetimibe?
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pregnant (C), and severe hepatic disease
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What 3 lipid-lowering drugs are pro-drugs?
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lovastatin, simvastatin, and fenofibrate
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Which statin is the least/most potent?
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most potent: pitavastatin
least potent: fluvastatin |
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(Biochem/genetics): What is a primary disorder of the ventricular muscle that is inherited in an autosomal dominant pattern and caused by 1 of 8 mutations to a sarcomere protein?
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hypertrophic cardiomyopathy
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(Biochem) What is the KEY to heart disease?
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lipid metabolism
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What is the problem in type 1 hyperlipoproteinemia?
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1. deficiency of LPL results in massive accumulation of chylomicrons, TG
2. Alternatively, an apoCII deficiency (AR) as it is a necessary cofactor to LPL. results in same clinical problem |
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What is the clinical chemistry of LPL/Apo CII defect?
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type 1
increased chylomicrons and TG's |
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What is the problem seen in familial hypercholesterolemia?
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type IIa hyperlipoproteinemia
autosomal dominant defects in LDL-R heterozygotes have high T-C and LDL, but not as high as homozygous |
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What are the 2 important regions on the LDL-R gene that are subject to critical point mutations?
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ligand binding and EGF precursor homology regions (both extracellular portions of protein)
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What are the 5 classes of LDL receptor defects and their respective consequences?
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• Class 1: Null alleles
- failure to produce protein • Class 2: Transport-defective alleles - protein blocked between the ER and Golgi • Class 3: Binding defect alleles - protein fails to bind LDL • Class 4: Internalization-defect alleles - protein unable to cluster in clathrin-coated pits • Class 5: Recycling-defect alleles - protein unable to discharge the ligand and recycle |
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What is the 'clinical chemistry' of LDL receptor defects?
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type IIa
increases LDL and T-C |
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What isoform of ApoE has a low affinity for its receptor?
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e2 isoform
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What is the problem in type III familial dyslipidemia?
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low-affinity isoforms of ApoE results in lower affinity for LDL receptors and results in inc. LDL, T-C and TG's
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What apoprotein is important for lipid metabolism in the nervous system?
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Apo E (synthesized by brain astrocytes)
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What ApoE isoforms result in increased risk for atherosclerosis and Alzheimer's?
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e2 and e4 isoforms: atherosclerosis
e4: alzheimer's disease |
