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109 Cards in this Set
- Front
- Back
What are the most effective drugs in treating dylipidemias?
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Statins
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What is the MOA of statins?
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Competitively inhibit the rate limiting ezyme in cholesterol biosynthesis, HMG-CoA reductase, thereby reducing synthesis of cholesterol
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What is the function of pancreatic lipase?
Which cofactor is required for its function? |
It requires colipase
Binds to the emulsified droplets and metabolizes triglyceridese into monoglycerides and fatty acids. |
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What are micelles composed of?
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Monoglycerides, fatty acids, phospholipids, and bile salts
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Which enzyme digests cholesteryl esters?
What are the products? |
Cholesteryl ester hydrolase
Products: cholesterol and fatty acids |
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Cholesterol interacts with which receptor protein for absorption?
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Niemann-Pick C1-like 1 protein (NPC1L1)
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Where are apoproteins synthesized?
Once made, where do they move? |
Rough endoplasmic reticulum (RER)
*Move to the smooth ER |
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What are the largest plasma lipoproteins?
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Chylomicrons
(they are also the least dense-- 98-99% lipid) |
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What are the chylomicrons made up of?
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1. Triglycerides (85%)
2. Apoproteins 3. Phospholipids 4. Cholestyryl esters |
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Why are blood lipid levels only tested after a 12 hour fast?
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Because you don't want chylomicrons to distort the blood lipid levels
(chylomicrons are present in plasma for 3-6 hours, and are not completely gone for 12 hours) |
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How are chylomicrons metabolized?
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As they travel through circulations, tissues that synthesize lipoprotein lipase partially metabolize them
Tissues: 1. Skeletal/ cardiac muscle 2. Adipose tissue 3. Breast tissue of lactating women |
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What does lipoprotein lipase digest and what are the products?
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Chylomicrons
1. Free fatty acids 2. Glycerol (Remaining portions of chylomicrons are called chylomicron remnants) |
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Which apoprotein component is trasnferred onto chylomicrons, and what is the function of this?
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ApoE (transferred from HDLs)
*This component binds to receptors on hepatocytes, allowing the liver to remove chylomicron remnants from the blood |
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Which two receptors bind ApoE components on chylomicrons?
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1. Low density lipoprotein receptors (LDLR)
2. LDL receptor-related protein (LRP) |
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What sort of process allows hepatocytes to absorb chylomicron remnants?
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Receptor-mediated endocytosis
(accomplished by ApoE binding to LDLR and LRPs) |
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What sort of transfer process allows absorption of long chain fatty acids and triglycerides into the intestinal epithelial cells?
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Diffusion
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What happens to the monoglycerides and fatty acids that are absorbed into the intestinal epithelial cells?
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They are reformed into triglycerides
(this maintains diffusion gradient for more free acids and monoglycerides to be absorbed) *The triglycerides are then moved to the SER |
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Which enzyme reesterifies cholesterol that is absorbed into intestinal epithelial cells?
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Acyl coenzyme A: cholesterol acyltransferase (ACAT)
*This maintains absorption gradient for cholesterol absorption *The resultant cholesterol esters are moved to the SER |
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What happens once cholesterol esters and triglycerides are moved to the SER?
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SER packages them into nascent (precursor) chylomicrons, which then move to the Golgi apparatus.
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What happens to chylomicrons once they are created?
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They leave the small intestinal epithelial cell by exocytosis.
*They are too large to enter capillaries, so they are taken up by the lacteals and enter the bloodstream via the thoracic duct |
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Within chylomicrons, are there more triglycerides or more cholesteryl esters?
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Triglycerides make up the majority of chylomicrons
(TG : CE ration is 10) |
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How do hepatocytes regulate cholesterol levels in the body?
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By controlling its synthesis
(based on the levels of cholesterol in the hepatocytes) |
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What is the rate-limiting step of cholesterol synthesis?
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HMG-CoA reductase
*converts 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate |
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What is the primary way the liver gets rid of excess cholesterol?
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Cholesterol is converted to bile salts and enters the enterohepatic circulation
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What are VLDLs composed of, and where are they made?
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1. Cholesterol
2. Cholesteryl esters 3. apoB-100 4. TGs 5. Phospholipids *Synthesized in the liver and secreted by exocytosis into the blood stream |
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How are VLDLs metabolized?
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They are partially metabolized in the blood stream (like chylomicrons) by lipoprotein lipase into monoglycerides and free fatty acids which are taken up by the tissues
*Produces VLDL remnants --> Intermediate-density lipoproteins |
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VLDL remnants are also termed what?
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Intermediate-density lipoproteins (IDLs)
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What are the 2 major fates of IDLs?
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1. Can be recycled into the liver
2. Can interact with hepatic lipase |
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Describe how IDLs interact with hepatic lipase?
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Hepatic lipase partially digests IDLs, releasing monoglycerides and fatty acids that are then taken up by the liver.
ApoE is removed *The resulting lipoproteins are termed low-density lipoproteins (LDLs) |
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What are the 2 major fates of LDLs?
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1. Recycled into the liver
2. Taken up by cells in the other body tissues. |
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The apoB-100 can only bind to which receptor?
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LDLR
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Nascent HDLs are created by which organs?
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1. Liver
2. Small intestines |
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What is the major apoprotein in HDLs?
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apoA-1
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Cholesterol that is floating around in blood can be esterified by an enzyme contained in HDLs-- what is this enzyme?
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Lecithin-cholesterol acyltransferase (LCAT)
*HDLs incorporate resultant CEs into their centers |
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The liver delivers TGs and cholesterol to other tissues in the form of...?
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VLDLs
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What is the function of HDLs?
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Take up excess cholesterol from tissues and transfer it to VLDLs, IDLs, chylomicrons, and the liver.
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How is the synthesis of LDLR regulated?
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High cholesterol levels in the liver downregulate its synthesis
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How is HMG-CoA reductase regulated?
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By cholesterol levels in hapatocytes-- classic negative feedback
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How much cholesterol is excreted each day in stools, and what in what forms?
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1g of cholesterol
1/2 in form of bile acids 1/2 in form of reduced cholesterol, coprosterol |
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How much cholesterol is absorbed from meals?
Consequently, how much cholesterol must be synthesized by the liver? |
0.2 g is absorbed from meals
0.8 g must be synthesized by the liver to make up for the extreted cholesterol |
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What are the major lipid components of plaques?
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Cholesterol and its esters
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What are the major carriers of cholesterol in the blood?
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LDLs
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What is the current recommendation for total cholesterol level?
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<200 mg/dl
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What is the current recommendation for LDL-C levels?
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<130 mg/dl
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What is the current recommendation for HDL-C levels?
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>40 mg/dl for MEN
>50 mg/dl for WOMEN |
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What is the current recommendation for the ratio of total cholesterol to HDL-C?
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5:1
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What is the current recommendation for the ratio of LDL-C to HDL-C?
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3:1
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What is the optimal level of LDL-C?
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<100 mg/dl
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Which range of total cholesterol levels is defined as "borderline to high"?
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200-239 mg/dl
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Which range of total cholesterol levels is defined as "high"?
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>240 mg/dl
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Which range of LDL-C is defined as "borderline to high"?
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130-159 mg/dl
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Which range of LDL-C is defined as "high"?
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>160 mg/dl
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Triglycerides should be less than what value for the desirable range?
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<120 mg/dl
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Which levels of TGs are defines as "borderline to high?'
How about "high"? |
120 - 199 mg/dl --> borderline to high
>200 mg/dl --> HIGH |
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What condition can be caused by TG levels above 1000 mg/dl?
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Pancreatitis
*Major problem with high TGs |
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What are xanthomas?
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Tumor masses of lipids contained in foam cells
*Associated with plasma levels greater than 300 mg/dl |
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What is the problem behind primary chylomicronemia?
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Deficiency of lipoprotein lipase
*Chylomicrons cannot be metabolized Leads to SEVERE LIPEMIA (2000-3000 mg/dl of TGs) |
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Which disease may not be discovered until a patient has an acute attack of pancreatitis?
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Primary chilomicronemia
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Is primary chylomicronemia autosomal dominant or recessive?
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Recessive
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Which disease results from a failure to adequately remove triglyceride-rich lipoproteins?
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Familial hypertriglyceridemia
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Which condition leads to increased levels of VLDL, LDL, or both?
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Familial combined hyperliporoteinemia
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Are xanthomas typically present in familial combined hyperlipoproteinemia?
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No
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Are xanthomas typically present in familial hypertriglyeridemia?
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Yes
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Are xanthomas generally present in primary chylomicronemia?
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Yes
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Which condiition results from a defect in apoE synthesis?
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Familial dysbetalipoproteinemia
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What is the problem behind familial hypercholesterolemia?
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Mutations in the LDL receptor, which prevents cholesterol uptake into the liver
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Is Familial hypercholesterolemia autosomal dominant or recessive?
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Dominant
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Describe the different total cholesterol levels of those who are heterozygous and those who are homozygous for Familial hypercholesterolemia
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Heterozygous --> 250- 500 mg/dl
Homozygous --> above 1000 mg/dl *Total cholesterol should be <200 mg/dl |
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What sort of trigylceride levels are present in people with Familial hypercholesterolemia?
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Normal
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Which condition results from damaged ApoB-100?
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Familial ligand-defective apolipoprotein B
*Impairs binding of LDLs to hepatocytes and other cells, so plasma LDLs increase. |
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What is the significance of liporotein(a)?
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It is found in atherosclerotic plaques and is associated with higher risk coronary artery disease
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What is the result of HDL deficiency?
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Increased atherosclerosis
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Which genetic disorders are associated with HDL deficiency?
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1. Tangier disease
2. LCAT deficiency 3. Familial hypoalphalipoproteinemia |
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Which conditions can lead to both hypertriglyceridemia and hypercholesterolemia?
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1. Excess corticosteroids
2. Hypopituitarism |
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Does diabetes mellitus lead to hypertriglyceridemia or hypercholesterolemia?
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Hypertriglyceridemia
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Does alcoholism lead to hypertriglyceridemia or hypercholesterolemia?
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Hypertriglyceridemia
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Does anorexia nervosa lead to hypertriglyceridemia or hypercholesterolemia?
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Hypercholesterolemia
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Does hypothyroidism lead to hypertriglyceridemia or hypercholesterolemia?
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Hypercholesterolemia
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Does obesity lead to hypertriglyceridemia or hypercholesterolemia?
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Hypertriglyceridemia
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What are the main dietary components that increase LDL?
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1. Cholesterol
2. Saturated fats 3. trans-fats |
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What are the main dietary components that increase triglycerides?
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1. Total fat
2. Alcohol 3. Excess calories |
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Dietary fat intake should be limited to what percentage of daily caloric intake?
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20 - 25% of daily caloric intake
(Saturated fats no more than 8%) |
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What type of fat is recommended for reducing blood lipid levels?
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cis-monosaturated fats
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People with high VLDL and IDL should especially be aware of what sort of dietary limitations?
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1. Avoid alcohol
2. Restrict caloric intake |
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How do statin drugs affect the regulation of LDLR and what is the result?
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Statin drugs decrease the synthesis of cholesterol, which upregulates LDLRs.
*This results in increased uptake of LDLs into the liver, decreasing plasma LDLs |
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What is the effect of statins on LDL, VLDL, IDL, triglyceride, and HDL levels?
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Decreases ---> LDL, VLDL, IDL
At high doses, can decrease triglyceride levels May increase HDL |
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List 3 statin drugs approved for use.
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1. Lovastatin
2. Simvastatin 3. Pravastatin |
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What is the prototype statin?
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Lovastatin
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How is Pravastatin unique?
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It is metabolized differently than the other statins
So if a patient has trouble tolerating the others, this may be a useful alternative. |
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List 5 cardioprotective effects of statin drugs.
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1. Improves endothelial function (facilitates NO production)
2. Enhance stability of plaques 3. Reduce inflammation 4. Reduce oxidation of lipids in vascular wall 5. Reduce platelet aggregation |
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What are 2 adverse effects of statins?
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1. Myopathy
2. Rhabdomyolysis |
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Conditions that increase plasma levels of statins can lead to ______.
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Myopathy
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Which drug blocks uptake of statins into the liver, increasing plasma levels of statins?
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Gemfibrozil
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What are the safest antilipidemic drugs?
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Bile acid resins
(they are not absorbed from the GI tract) |
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What is the MOA of bile acid resins?
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They are (+) charged and bind to (-) charged bile acids, inhibiting bile acid reabsorption.
*Results in increased bile acid synthesis, reducing the amount of cholesterol in the liver |
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What is the effect of bile acid resins on HMG-CoA reductase and LDLR synthesis?
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Both are increased
Increased LDLR synthesis decreases plasma LDL, but this is curbed a bit by the increased cholesterol production |
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How can the effectiveness of bile acid resins be improved?
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By pairing them with a statin
(this will reduce production of cholesterol) |
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What is the MOA of Niacin? (4)
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1. Inhibits lipolysis of triglycerides in adipose tissue
*Fewer free fatty acids are delivered to the liver 2. Inhibits synthesis and esterification of fatty acids in the liver *Both effects prevent the liver from producing VLDLs, which reduces LDLs 3. Increases the activity of lipoprotein lipase 4. Reduces clearance of apoA-I (increases HDLs) |
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Why should Niacin not be used in most patients?
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Serious adverse effect: HEPATOTOXICITY
*2g of Niacin is commonly needed to produce therapeutic effect; however, this dose of Niacin makes patients particular susceptbile to liver failure |
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Which drug blocks cholesterol absorption by interfering with the NPC1L1 transport protein?
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Ezetimibe
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How is the effectiveness of Ezetimibe limited?
How can the effectiveness be increased? |
This drug blocks the intestinal absorption of dietary cholesterol, which leads to increased endogenous production of cholesterol
*Often paired with a statin to increase effectiveness |
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What do fibrate derivatives activate?
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PPAR transcription factors
(peroxisome proliferator activated receptors) |
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List one drug in the class of fibrate derivatives.
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Clofibrate
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What is the MOA of Clofibrate?
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Activation of PPAR, which facilitates fatty acid oxidation and synthesis of LPL are facilitated.
*Reduction of triglycerides in plasma |
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Which group of drugs are the first choice for treating severe triglyceridemia?
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Fibrates
(Clofibrate) |
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The combination of which 2 drugs can lead to myopathy and rhabdomyolysis?
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1. Fibrates (esp. Gemfibrozil)
2. Statins |
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Give one example of a bile acid resin.
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Cholestyramine
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Diet alone cannot adequately treat which 2 conditions?
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1. Familial hypercholesterolemia
2. Familial combined hyperlipidemia |
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What kind of factors may increase the plasma levels of statins?
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1. * Hepatic or renal dysfunction/ disease
2. Age 3. Diabetes 4. Small body 5. Hypothyroidism |