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134 Cards in this Set
- Front
- Back
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What makes up the core and surface of lipoproteins?
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core - cholesteryl esters, TGs
surface - monolayer of more polar lipids (phospholipids, unesterified cholesterol) proteins (enzymes, apolipoproteins) |
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What are the two pathways by which our bodies get lipoproteins? Which organ is central to both pathways?
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Exogenous - lipid from diet
Endogenous - synthesized by body Organ involved = liver |
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Does the body ever stop making lipids?
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No, even if there's excess lipid in diet, there is still synthesis by the body
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Where are bile salts made and how are they used?
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Synthesized by liver from cholesterol
Secreted into intestine after ingestion of food |
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What do bile salts do in the intestine? What happens after that?
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Solubilize dietary TGs which are hydrolyzed by pancreatic lipases which then diffuse into intestinal epithelial cells
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What happens to the bile acid left in the intestines?
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Majority is absorbed further down intestine. Some is lost in feces.
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How are chylomicrons made?
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Enterocytes package re-synthesized TGs and dietary cholesterol together to form a large diameter, low density chylomicron which enters the lymph and then blood.
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What is the make-up of a chylomicron?
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TG > 90%
cholest ester+cholest < 5% Phospholipids 5-10 % Protein 1-2 % Fat soluble vitamins |
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What are initially the only form of chylomicrons? What do they acquire after that?
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Initially apo B-48
In circulation acquire apo E and apo C’s |
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What's the half-life of a chylomicron? What's a consequence of this?
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Half life 5-30 mins.
Can get huge fluctuations in levels |
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What hydrolyzes TGs in circulation?
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lipoprotein lipase (LPL) = decreases the size of chylomicrons
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Where is lipoprotein lipase (LPL) located?
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Primarily on surface of capillaries of adipose and muscle tissue.
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What activates lipoprotein lipase?
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apo CII
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What are TG's hydrolyzed to by lipoprotein lipase?
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Free fatty acids (used for energy or re-esterified) and glycerol
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What happens as chylomicrons shrink?
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Transfer of apo C and most apo E to HDL. When all apo C’s are lost, they become Chylomicron remnants and LPL is no longer activated = minimal hydrolysis of TG’s
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What's the make up of chylomicron remnants and what happens to them?
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More Cholesterol Esters than TG.
Remnants are taken up by liver. (Very short half life = 5 min) |
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What's the half life of VLDL and where's it made?
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Half life ~ 12 hours
Synthesized in the liver |
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What's the make-up of VLDLs?
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Usually 50 – 70 % TG (from fat and carbs)
C 8-10 %, CE 12-15 % (dietary and synthesized) |
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What apo's does VLDL have?
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Apo C’s, apo E and apo B100
Some of apos from HDL including apo CII and apo E |
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What happens as VLDLs decrease in size due to TG hydrolysis by LPL?
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Become IDL (intermediate density lipoprotein).
Lose apo’s including apo CII = reduced rate of removal of TGs |
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What's the make up and fate of IDL?
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TG = CE
About 50% of IDL taken up by liver (Receptors recognizes apo E and apo B-100?) Short half life – mins to an hr |
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What happens to the IDL that isn't taken up by the liver?
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Looses more TG and becomes
LDL (low density lipoprotein) |
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What is the function and make-up of LDL?
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Primary carrier of cholesterol
TG’s = 5%, C + CE = 70%, protein = 20% |
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What the major apolipoprotein for LDL?
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apo B-100
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Half-life and importance of size for LDLs?
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Half life is ~ 2.5 to 3 days
Range of sizes, smaller more atherogenic |
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Where apo B-100 found? What's it's effect on cardiovascular disease?
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Component of VLDL, IDL, LDL
Increase is positively correlated with and increase in CVD |
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What is the familial defect in apo B?
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Glutamine 3500 for arginine (one of the most common mutations in humans)
Affects binding to receptor, affinity 3-5 % of normal |
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What is the receptor for apo B-100 and where is it found?
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The LDL receptor
Found in both hepatic and extrahepatic tissues |
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What happens after apo B-100 binds the LDL receptor?
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Receptor – LDL complex is endocytosed and cholesterol is de-esterified and released as free cholesterol in cytoplasm
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What happens to the free cholesterol in the cytoplasm created from the break down of LDL?
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Some of the cholesterol goes to membranes and the excess is re-esterified by ACAT (acyl-CoA-cholesterol acyltransferase)
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What are the functions of acyl-CoA-cholesterol acyltransferase? (where do these occur?)
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Important in...
Intestine:cholesterol absorption Liver: production/release VLDL Cell: storage and secretion Foam cell formation and atherogenesis |
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What are the two major ways the body regulates cholesterol?
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1. Dec cholesterol synthesis
2. Dec rate of LDL receptor transcription (= less cholesterol uptake) |
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What happens as the level op cholesterol in cells increases?
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There is less removal of LDL and IDL = increase in the levels of circulating cholesterol and cholesterol ester.
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What is the problem in familial hypercholesterolemia?
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Mutations in LDL receptor:
Some have less receptors (usually impaired cell processing) Most have impaired function (normally receptors are high affinity and very efficient) |
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What's the incidence and consequences of heterozygous familial hypercholesterolemia?
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1 in 500
Serum cholesterol often up to 2x normal and about 5% have MI before age 60 |
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What's the incidence and consequences of homozygous familial hypercholesterolemia?
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1 in 1,000,000
Serum cholesterol high Signs of CVD at an early age, most have an MI by age 20 |
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Where's HDL synthesized and what's it's make-up?
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Synthesized in liver and small intestine
Major component apoA1. Has other apo A’s, C’s and E plus antioxidants |
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What does it mean to say HDL is dynamic?
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Heterogenous. Exchanges apo’s with lipoproteins (mainly IDL and chylomicron remnants)
and cholester from cells in periphery |
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What's LCAT and what does it do?
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lecithin cholesterol acyl transferase
Esterifies cholesterol - ester moves to the interior and the particle enlarges. |
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What's the co-factor for LCAT?
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Apo A1
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What's CTEP and what does it do?
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Cholesteryl ester transfer protein
Transfers CE to other lipoproteins (cf torcetrapib) |
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What does HDL do?
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Transfers lipids and apolipoproteins between particles as well as back to liver, and cells in the periphery (particularly the ovaries and adrenals for steroidgenesis).
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What are 2 enzymes associated with HDL?
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LCAT
CTEP |
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What's HDLs affect of CVD risk?
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Strong correlation between increased HDL and decreased CVD risk
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What's the relationship between CTEP and CVD?
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evidence that lower CTEP activity lowers future risk of cardiovascular events
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What's Torcetrapib?
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CTEP inhibitor- increases HDL and lowers LDL, increasing mortality
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What happens when the LDL particle is modified by something like oxidation?
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Macrophages can take up a lot of them and become foam cells via a scavenger receptor that recognizes altered apo B-100s
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How does LDL get oxidized?
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Oxygen radicals react with lysines on the apo B-100 (also converts unsaturated FAs to aldehydes and oxides)
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Can HDL get oxidized?
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Yes but it has at least 2 antioxidant enzymes that inhibit/reverse oxidation
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What type of disorder is atherosclerosis?
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An inflammatory disorder
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What are the classifications of the levels of LDL?
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<100 Optimal
100-129 Near optimal 130-159 Borderline high 160-189 High ≥190 Very high |
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What are the classifications of the levels of total cholesterol?
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<200 Desirable
200-239 Borderline high ≥240 High |
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What are the classifications of the levels of HDL?
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<40 Low - men
<50 women ≥60 High |
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What major risk factors modify LDL goals? (4)
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1. Cigarette smoking
2. Hypertension (BP≥140/90 mmHg or on antihypertensive medication) 3. Low HDL cholesterol 4. Family history of premature CHD (male first-degree relative <55 yrs or female <65 yrs) |
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How does an HDL > 60 mg/dL change the LDL goals?
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Counts as a negative risk factor: removes one risk factor from the total count
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What are the LDL goals if you have 0-1 risk factors? At what level should you consider drug therapy?
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Goal <160 mg/dL
Tx if ≥190 mg/dL |
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What are the LDL goals if you have 2+ risk factors? At what level should you consider drug therapy?
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Goal <130 mg/dL
TX if ≥130 mg/dL for 10 yr risk of 10-20% ≥160 mg/dL for 10 yr risk < 10% |
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What are the LDL goals if you have CHD/CHD risk equivalent or 10 year risk >20%? At what level should you consider drug therapy?
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Goal <100 mg/dL
Tx if ≥130 mg/dL |
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What is a CHD risk equivalent?
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Clinical CHD, symptomatic carotid artery disease, peripheral artery disease, or abdominal aortic aneurysm
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How are 10 year risks calculated?
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% risk calculated using Framingham point scores
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What are the classifications for serum triglyceride levels?
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<150 Normal
150 - 199 Borderline high 200 - 499 High ≥500 Very high |
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What the significance of High Sensitivity C-reactive protein?
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Marker of inflammation
Suggested to be a predictor of future cardiac events and be a stronger predictor than LDL. |
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Is hsCRP used to determine CVD risk?
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No, not current recommended for primary risk detection
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What are the secondary causes of dyslipidemia?
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Diabetes, alcoholism, hypothyroidism, estrogen nephrotic syndrome, protease inhibitors (HIV), isoretinoin
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How does one make the diagnosis of metabolic syndrome?
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Any 3 of following risk factors:
1. Abdominal obesity – men >40”, women > 35” 2. TG >150 mg/dL 3. HDL <40 (men), <50 (women) 4. BP >130 / >85 mm Hg 5. Fasting glucose >100 mg/dL |
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Which type of diabetics are at high risk for CVD?
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Both 1 and 2
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How does insulin effect cholesterol levels?
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Insulin enhances transcription of LPL (lipoprotein lipase)
= Increased removal of TG’s = decrease in VLDL |
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What happens to cholesterol levels if the patient has low insulin or is insulin resistant?
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Decreased LPL leads to increased VLDL
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What are the 4 main therapies to control cholesterol?
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Diet
Exercise Tx of primary conditions that = secondary hyperlipidemias Drugs |
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Name 6 HMG-CoA reductase inhibitors?
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lovastatin
simvastatin pravastatin fluvastatin atorvastatin rosuvastatin |
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What are the effects of HMG-CoA reductase inhibitors on TGs, LDL, and HDL?
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TGs = decreased or not affected
LDL = decreased HDL = increased or not affected |
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What are the side effects of HMG-CoA reductase inhibitors?
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Low incidence of myopathy, liver damage
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What is the mechanism of action for HMG-CoA reductase inhibitors? What's the direct effects of this?
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inhibits HMG-CoA reductase =
↓ cholesterol synthesis ↑ hepatic LDL receptor synthesis ↑ uptake of LDL |
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What time of day are HMG-CoA reductase inhibitors most effective? Why?
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Night time
The majority of cholesterol synthesis occurs at night |
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What do HMG-CoA reductase inhibitors require to work?
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Need to have functional LDL receptors
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What situation are HMG-CoA reductase inhibitors useful in?
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Useful in secondary hypercholesterolemia due to diabetes
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How can HMG-CoA reductase inhibitors help in people with high hsCRP?
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Pts with high levels of hsCRP but normal cholesterol have a decreased risk of CVD.
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Which drug react with the metabolism of HMG-CoA reductase inhibitors? (which specific statins does this affect?)
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Cyclosporin, erythromycin, ketaconazole, niacin, fibrates, St Johns wort, dihydropyridine Ca channel blockers, grapefruit juice.
(Lovastatin, simvastatin, atorvastatin) |
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How is the metabolism of Lovastatin, simvastatin, atorvastatin affected by grapefruit juice, sporins, azoles, etc?
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Drugs compete for clearance by
P450A (CYP3A4) = increased half life and increased concentration = increases risk of myopathy |
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What drug levels are increased by HMG-CoA reductase inhibitors?
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Oral contraceptives, digoxin and warfarin
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How do bile acid-binding drugs (resins and ezetimibe) effect HMG-CoA reductase inhibitors?
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Addititve LDL decreases by increasing statin activity
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What are the effects of HMG-CoA reductase inhibitors on coenzyme Q10?
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May lower levels, causing myopathies (especially in elderly patients)
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Which of the HMG-CoA reductase inhibitors is not as effective in women in decreasing the rate of coronary events?
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Atrovastatin
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What are the effects of HMG-CoA reductase inhibitors on bone density, alzheimers/dementia, and the immune system?
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Increase bone density = dec fractures (may stim osteoblasts)
? risk of dementia Anti-inflammatory |
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Name 2 Bile acid-binding resins?
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cholestyramine
colestipol |
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What is the effect of Bile acid-binding resins on TG, LDL, and HDL?
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TG = often increased then dec
LDL = decreased HDL = no effect |
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What are the side effects of Bile acid-binding resins?
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GI = nausea, indigestion, constipation
Hyperchloremia acidosis (inc Cl) |
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Mechanism of action of Bile acid-binding resins? Effects of this?
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Bind bile acids leading increased fecal excretion...
Liver compensates by increasing bile acid synthesis and secretion = up regulation of LDL receptors = increase in uptake of LDL from plasma. |
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What is a requirement of Bile acid-binding resins?
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Functional LDL receptors
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What interactions do Bile acid-binding resins have with other drugs?
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Bind other drugs in gut like anticoagulants and digitalis (dose at different times)
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What is the effect of Bile acid-binding resins on vitamin uptake?
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Fat soluble vitamin uptake may be impaired - A, D, E and K. (supplement 1-4 hrs after resin)
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What drugs do Bile acid-binding resins potentiate the effects of?
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niacin and statins
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What is Colesevelam?
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Bile acid-binding drug taken as a pill rather than a resin = may increase compliance but dosing is 3 large pills BID
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What's one advantage of Colesevelam with regards to side effects?
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Doesn't interfere with the absorption of fat soluble vitamins or most drugs.
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What is the effect of Niacin (NICOTINIC ACID) on TGs, LDL, and HDL?
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TG = rapid 20-80% decrease depending on VLDL levels
LDL = 10-25% decrease (up to 50% with an acid-binding resin) HDL = variable increase |
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What are the side effects of Niacin? (what can help with this?)
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Low compliance due to itching and flushing.
Long acting = less of a problem but some have increased hepatotoxicity. (Start with a reduced dose and take with aspirin) |
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What is the mechanism of action for Niacin?
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unclear, suggested to inhibit a hormone-sensitive lipase
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What are the drug reactions for Niacin?
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may potentiate anti-hypertensives
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Name 2 Fibrates?
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Gemfibrozil
Fenofibrate |
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Fibrates effects of TG, LDL, and HDL?
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TG = 40-50% decrease (mainly VLDL)
LDL = decrease HDL = increase |
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Side effects of Fibrates?
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GI and possible mild hyperglycemia with diabetics
Low level of myopathy |
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Mechanism of action for Fibrates?
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activator of PPAR alpha
Increased LPL activity = increased TG clearance (decreased VLDL). Also increase the proportion of larger LDL particles |
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Drug interactions of Fibrates?
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displaces drugs from albumin = inc effect of anticoagulants, phenytoin, tolbutamide
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Clinical use of Fibrates?
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Most hypertriglyceridemias
Effective in diabetics, both reducing C and TG’s and changing composition. |
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What is Trilipix?
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new delayed release fenofibrate, formulated for use with statins
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What CP metabolizes Fibrates?
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CYP3A4 (also metabolizes some statins)
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What is Clofibrate?
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A fibrate that is less effective than other fibrates in lowering TG and raising HDL.
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What's bad about Clofibrate?
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Studies showed increased death over placebo,
due to no decrease in number of MI and a higher incidence of neoplasms. |
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Clinical use of Clofibrate?
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only when other drugs aren't effective
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What's Ezetimibe (Zetia)?
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Newer class of selective cholesterol-absorption inhibitors
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Mechanism of action for Ezetimibe (Zetia)?
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Blocks intestinal absorption of dietary and biliary
cholesterol, without affecting absorption of fat soluble vitamins or triglycerides. |
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Side effects and drug interactions of Ezetimibe (Zetia)?
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No side effects or major drug interactions reported.
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Clinical use of Ezetimibe (Zetia)?
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Combined with statins or fibrates to further decrease LDL
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What is vytorin? What's it's efficacy?
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simvastatin (Zocor) + ezetimibe
shown to lower LDL more than Zocor alone but no difference in arterial plaque growth |
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What's Orlistat used for?
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Treatment of obesity
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Effects of Orlistat on TG, LDL, and HDL?
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TG = decreased
LDL = decreased HDL = no change |
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Side effects of Orlistat?
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GI- related to amount of fat in diet = Gas, urgency, diarrhea, fatty stools
Reduces absorption of vitamins A, D, E, K and beta carotene |
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Mechanism of action for Orlistat?
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lipase inhibitor so decrease in intestinal fat absorption
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Drug reactions for Orlistat?
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no major ones
Recommended no other drug to be taken within several hours of taking orlistat |
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BMI needed to use Orlistat?
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30+
27 with other risk factors |
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What effects do the Omega-3 acid ethyl esters have on lipids?
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Lowers triglycerides
(may increase LDL but improved profile) Reduces levels of postprandial chylomicrons and VLDL |
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Mechanism of action of Omega-3 acid ethyl esters?
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Thought to reduce production of TG in liver
May be anti-inflammatory |
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What's the effect of Omega-3 acid ethyl esters on clotting?
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Thought to reduce production of thromboxane(involved in clumping of platelets)
Take with anticoagulants |
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What's the Omega-3 intake recommendation for patients without documented CHD?
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Variety of oily fish twice a week plus foods with alpha-linolenic acid (flaxseed, canola, soybean oils and walnuts)
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What's the Omega-3 intake recommendation for patients with documented CHD?
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I gm EPA+DHA per day (preferably oily fish but supplement ok)
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What's the Omega-3 intake recommendation for patients with high TGs?
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2-4gm EPA+DHA per day via supplementation
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What foods are good for lipid health?
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Fish oil (walnuts, flax/linseed)
Soy Margarines (Benecol, Take Control) Avocado Red wine or alcohol? Other nuts? Fiber (Fruit & vegetables for antioxidants) |
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What is ursodiol?
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A gallstone solubilizing agent
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Mechanism of action and clinical use for Ursodiol?
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Dissolution of radiolucent
gallstones - Increases concentration at which saturation of cholesterol occurs, so slowly dissolve |
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Drug interactions of Ursodiol?
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Antacids and bile acid-binding resins may interfere with absorption.
Agents such as estrogens may counteract since they encourage stone formation |
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Name 2 Gallstone solubilizing agents?
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Ursodiol
Monoctanoin |
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What is Monoctanoin?
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Gallstone solubilizing agent
Semisynthetic esterified glycerol |
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Mechanism of action and clinical use for Monoctanoin?
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For gallstones remaining in biliary tract after cholecystectomy. Perfusion of bile duct for 2-10 days
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Side effects of Monoctanoin?
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GI
Fever |
