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64 Cards in this Set

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  • Back
Chylomicron function?
Carries dietary lipids (cholesterol and triglycerides) from the GI tract to the liver and other tissues of the body.
VLDL, IDL, and LDL function?
Carry endogenously-synthesized lipids from the liver to other tissues of the body
HDL function?
-- Carries cholesterol from non-hepatic tissue back to the liver

-- Scavenges free cholesterol from the plasma and cells of the intimal wall of arteries
What is the daily "dose" of lipids which the intestines must metabolize?
-- about 1200mg of cholesterol
-- 100mg of triglycerides

Triglycerides strictly from dietary origin but bulk of cholesterol (about 900mg) is synth by liver and delivered to GI tract via the 800-1000ml of bile produced daily

**Cholesterol synth by the liver greatly overshadows our dietary intake
Cholesterol absorbed vs. cholesterol lost?
About 600mg absorbed from GI tract each day

Other 600mg of cholesterol is lost in the feces as bile salts
How is cholesterol transported through blood to the liver and other tissues?
-- It must be converted to a water-soluble form for transport

-- Enterocyte contains acyl coenzyme A cholesterol acyltransferase (ACAT) which produces cholesterol esters which are packaged with TGs in chylomicrons for transport

**chylomicrons are the "trucks"
Explain the chylomicron pathway
Chylomicrons surface contains phospholipids and the apolipoproteins A-I, A-II, A-IV, and ApoB-48

Chylomicrons are collected into the chyliferous lymphatic capillaries and enter circulation via the thoracic duct.

Entry into circulation is accomp by the addition of ApoC-II, ApoC-III, and ApoE.

"Driver" of chylomicron is ApoB-48, and his helpers are ApoC-II and ApoE
What is the ratio of TGs/cholesterol in the chylomicron?
What is the purpose of the chylomicron?
-- Delivers dietary TGs (rich source of E) to cardiac and skeletal muscle for immediate use and to adipocytes for storage

-- also carries cholesterol to the liver
How is the chylomicron unloaded?
The enzyme lipoprotein lipase (LPL) is expressed on the surface of capillary endothelial cells in the striated muscle and fat cells.

-- ApoC activates the LPL and tells the LPL "workers" to unload the chylomicron "truck"

-- LPL unload the TGs by converting them to free fatty acids which can be reesterified for storage in adipocytes or used immediately via oxidation to create energy for striated muscle

-- LPL only unload TGs, and DO NOT unload any cholesterol from the chylomicrons

-- Some cholesterol spills out with the unloading, but most is delivered to the liver
What happens to the unloaded chylomicron?
-- Now called a remnant, is removed from the liver circulation in a manner of minutes

-- ApoE in the remnant is a recognition protein for binding of the remnant to the hepatic LDL-receptor-related protein (LRP)

-- ApoB-48 drives partially unloaded chylomicron to the liver, where ApoE recognizes the correct portals for entry

-- cholesterol is unloaded in the liver and becomes part of important steron pool
How do we get cholesterol and endogenously synth TGs from the LIVER to the rest of the body?
-- VLDL formed in the liver consists of TGs, cholesterol, phospholipids, and a single molecule of ApoB-100

-- ApoB-100 molecule MUST be assoc with the VLDL for secretion from the liver into the blood
Ratio of TGs/cholesterol in the VLDL?
CHOs and VLDL?
Increased intake of CHOs increases formation of VLDL particles

-- after high CHO meal, more of the VLDLs leave the liver and each is more heavily laden with THs

-- ApoB-100 leaves the liver and picks up the same helpers: ApoC-II, ApoC-III, and ApoE

-- in similar fashion to the chylomicrons, the LPL unliads TGs from the VLDL at adipocytes and striated muscle under the direction of ApoC-II
What happens after unloading of VLDL?
-- It is now called an intermediated density lipoprotein (IDL), and has different fate than the chylomicron remnant
Ratio of TGs/cholesterol in IDL?
What happens to the resultant IDL?
-- One-half of the resulting IDL particles are removed from the circulation via binding to the hepatic LDL receptor (requires ApoB-100)

-- Other half of the IDL particles are converted to LDL with the loss of ApoE

-- LDL only contain ApoB-100 and are removed from circulation via hepatic LDL receptors
Half lives of IDL and LDL?
IDL -- short, hours

LDL -- 2+ days
It is important to appreciate that 100% of plasma LDL comes from...
What about HDL? What does it do?
HDL cleans up the mess that LPL makes while unloading the chylomicrons and the VLDL

-- Unesterified cholesterol and other junk left behind, and HDL scavenges this junk

-- HDL synth in liver and small bowel and are coated with apolipoproteins ApoA-I and ApoA-II
What do ApoA-I and ApoA-II do?
They bind unesterified cholesterol attached to other lipoproteins (chylomicron remnants, VLDL) as well as free cholesterol found in the area of the vascular wall
What happens to the unesterified cholesterol after binding to the HDL?
It is esterified by the enzyme Lecithin cholesterol acyltransferase (LCAT) which transforms the cholesterol from polar to non-polar

-- Esterified cholesterol then moves to center of HDL particle, away from polar aqueous environment at the surface

-- leaves ApoA-I and ApoA-II free to bind more free cholesterol
What do the HDL particles do with their newly bound cholesterol?
They can either:

1. take it back to the liver

2. transfer it to VLDL and IDL particles via the enzyme cholesteryl ester transfer protein (CETP)
Why is LDL important in atherogenesis?
About 65-70% of total plasma cholesterol (Tc) is LDL.
-- it is the major atherogenic lipoprotein and oxidized LDL is especially atherogenic

Smaller LDL particles are more atherogenic than larger LDL particles

The higher the value of plasma TGs, the smaller and more atherogenic the LDL particles

elevated TGs = small LDLs = atherogenesis
What is the hepatic "sterolstat"?
Body has "sterolstat" that controls hepatic cholesterol synth based on supply and demand.
-- if dietary intake insufficient, the liver synth more cholesterol
-- if dietary intake leads to cholesterol stores in excess of need, liver doesn't synth or take up cholesterol

**plasma cholesterol concentration is maintained at some genetically-determined set-point, thus change in diet may not really make a large difference in cholesterol levels
Plasma [LDL] is controlled by...?
1. dietary intake of cholesterol

2. hepatic synth of VLDL

3. the number of LDL receptors expressed on the surface of hepatic and non-hepatic cells****
What can lower LDL receptor concentration?
1. increased p.o. ingestion of plant stanols

2. treatment w/ statins

3. treatment w/ ion-exchange resin

4. treatment w/ ezitimibe
How important are hepatic LDL receptors in removing LDL from circulation?
-- 75% of LDL removed from plasma is removed via LDL receptors

-- 65% of the total is removed by hepatic LDL receptors

-- Thus, hepatic LDL receptors remove 50% of plasma LDL
How, exactly, does the sterolstat work?
-- The genes which code for the hepatic LDL receptor and the HMG CoA reductase lie side-by-side, and their transcription is controlled by single promoter gene.

-- Activity of promoter gene is suppressed as long as a certain critical conc. of sterols is present within the hepatocyte

-- Cholesterol is one of the sterols which maintains this critical concentration

-- In decrease in dietary intake leads to depletion of this sterol pool below critical concentration, the promoter gene is no longer suppressed -- increased transcription of LDL receptors and HMG CoA reductase (rate limiting enzyme in chol synth)
What is the net effect of increased LDL/HMG transcription?
-- increased hepatic synth of cholesterol via increased HMG CoA reductase

-- increased uptake of cholesterol from plasma via increased number LDL receptors

-- liver compensates for lack of dietary intake by synth and capturing more plasma LDL

-- can't increase uptake of plasma LDL w/out ALSO increasing production of cholesterol, thus hepatic synth blunts the fall in plasma LDL conc whch results from increased expression of hepatic LDL receptors
How do you accurately determine the plasma LDL concentration?
You must draw blood after a patient had NPO overnight so that plasma TGs won't be high

Use Friedewald equation:

LDL = Tc - (HDL + TG/5)

It can now also be measured directly.
What are "normal" lipoprotein values?
LDL cholesterol:
-- <100mg/dl for moderately high-risk patients
-- <70mg/dl for very high-risk patients

HDL cholesterol:
-- >40mg/dl (>50 in women)

-- <150mg/dl

Conversion factors for SI units:
1mmol/L = 38.5mg/dl for HDL and LDL
1mmol/L = 88.6mg/dl for TGs
How do we estimate CV risk?
Risk is based on total cholesterol/HDL ratio (Tc/HDL) and absolute value of TGs after fasting

-- Low Tc/HDL plus low fasting TGs = clean arteries

-- High Tc/HDL plus high fasting TGs = atherogenesis

**major goal of therapy is to lower LDL
**other experts believe that the ratio of plasma [ApoB] tp [ApoA-I] determines CV risk
ApoA-I = HDL
What is the goal in treatment of hyperlipidemias or dyslipidemias?
1. Hyperlipidemia -- need to decrease Tc by decreasing plasma LDL and/or decrease plasma Tg concentration
hyperlipidemia = hyper[LDL]emia

2. Dyslipidemias - need to decrease the ratio of Tc/HDL by lowering the LDL and/or increasing the HDL

About 70% of patients w/ an adverse lipid profile and increased CV risk suffer from DYSlipidemia, not hyperlipidemia!
Can CAD exist in the presence of normal or low Tc?
YES! Other factors like HDL and TG levels play a part.
What are our strategies to improve the lipid profile and decrease CV risk?
1. Lower plasma LDL concentration
-- increase LDL receptors
-- decrease VLDL production
-- increase rate of VLDL clearance

2. Increase HDL concentration

3. Activate LPL in order to decrease TCs and thus make LDL particles larger and less easily oxidized

4. Decrease synth of ApoB and increase synth of ApoA-I
Inhibitors of HMG CoA reductase

Metabolic properties of the statins?
-- metabolized by CYP3A4

-- NOT metab by CYP3A4
-- excreted unchanged in the urine

-- NOT metab by CYP3A4
MOA of the HMG CoA reductase inhibitors (statins)?
-- inhib of sterol synth causes the intracellular sterol conc to fall, leading to increase in synth of HMG CoA reductase and LDL receptors
-- Induction HMG synthesis compensates for inhibition of enzyme, so sterol synth decreased by only 20-25%
-- Increased expression LDL receptors increases clearance of LDL and IDL from plasma
-- Increase in LDL receptors persists throughout treatment; however the increase in hepatic chol synth limits the fall in [LDL] caused by the increased expression of hepatic LDL receptors. Thus, increased synth of cholesterol appears unable to restore the intrahepatic sterol pool to normal, i.e. the sterolstat is not perfect

**Statins DO NOT lower plasma cholesterol in the genetic absence of hepatic LDL receptors (homo familial hyper cholesterolemia)

Statins produce the following changes in VLDL metabolism
1. decreased synth of ApoB-100 decreases hepatic VLDL production
2. increased clearance of VLDL from plasma; mech unknown
Combined treatment with other antilipemic drugs?
Statin + ezetimibe = LDL dec 40-45%

Statin + ion-exchg resin = LDL dec 50%

Statin + niacin = LDL dec 40%

Statin + resin + niacin = LDL dec 70%
What is the therapeutic indication for statin use?
everyone at risk including DMII
Other cardioprotective effects of statins?
1. reversal of endothelial dysfxn with improved ability to synth NO

2. decreased oxidation of LDL cholesterol

3. Increased stability of cholesterol plaques

4. Antiinflamm effect which produces fall in plasma conc of C-reactive protein (hs-CRP)
Statin toxicity?
1. hepatic damage
-- increased AST and ALT (0.1-0.5% patients)
-- check plasma AST and ALT before beginning treatment and at 6 and 12 weeks. After that, check semiannually

2. Myopathy = muscle pain/weakness
-- fatigue and progressive flu-like myalgia in arms and legs
-- biopsy reveals myofibrils negative for cytochrome oxidase and increased lipid stores, suggest mitoch dysfxn
-- myositis = 10x increase plasma CPK with or w/out myalgia on 0.1% of patients

3. Fatal rhabdomyolysis -- assoc w/ cerivastatin which was removed from market

4. Fetal toxicity - category X
Different incidence of myalgia with statins?
-- incidence increases during combined treatment of statin + gemfibrozil or niacin

-- Inhib of CYP3A4 by other drugs increases probability that simvastatin and atorvastatin will produce myalgia

-- CYP3A4 inhibitors include grapefruit juice, clarithromycin, fluconazole, fluoxeting, fluvoxamine, metronidazole, nefazodoe, sertraline, zafirlukast, verapamil, and amiodarone
Exetimibe pharmacokinetics?
1. rapidly absorbed, rapidly converted to active glucuronide conjugate w/in the intestinal wall, and concentrated in cells of the intestinal wall

2. extensive enterohepatic recirculation results in half life ~22h

3. about 80% of a p.o. dose is eliminated in feces
Ezetimibe MOA?
Increased hepatic LDL receptor expression via the sterolstat

1. blocks protein-mediated transporter which absorbs dietary cholesterol from GI tract

2. Does not inhibit the absorption of fat-soluble vitamins, TGs, estradiol, and progesterone

3. Cholesterol absorption from GI tract is decreased by ~50%

4. decreased delivery chol to liver depletes sterol pool

5. depletion sterol pool induces transcription of HMG and LDL receptors via sterolstat

6. Increased hepatic LDL uptake accounts for fall in plasma LDL

7. Increases hepatic chol synth by 80-90% but still does not seem to restore sterol levels fully, thus persistent elevation LDL receptors
What elses lowers [LDL] by same mech as ezetimibe?
Margarines Benechol, Take Control, and Smart balance contain plant stanol BETA-SITOSTEROL which lowers LDL by same MOA as ezetimibe
Simvastatin, ezetimibe, dosing, and myalgia....
1. statin alone decreases plasma [LDL] by 46% at it's highest dose of 80mg/dl
-- higher incidence of myalgia

2. LOWEST dose of simvastatin (10mg/dl) + EZE also decreases plasma [LDL] by 46%
-- lower incidence of myalgia
EZE therapeutic indications?
1. added to tx w/ statin when patients not able to achieve [LDL] goal w/ statin alone

2. Coadmin of EZE and statin allows large decrease in daily statin dose w/out losing its beneficial effects

3. Eliminates need to treat w/ ion-exchange resins to achieve further decrease in [LDL}
What is Vytorin?
EZE (10mg) + simvastatin (10, 20, 40, 80mg)
EZE toxicity?
1. When combined with statin, rist of asympt elev of AST and ALT increases, but risk less than 2%

2. Does NOT increase risk of myopathy when used w/ statin; risk w/ statins still there, but EZE does not compound risk

3. Has no effect on CYP1A2, CYO2D6, or CYP3A4, so NO DRUG-DRUG interactions!!

4. Pregnancy category C -- risk cannot be ruled out
What are the ion-exchange resins and what do they do?
Bind bile acids

colesevelan (6 large pills/day)
Resin MOA?
Increased hepatic LDL receptor expression via sterolstat

1. Anion exchange resins swap Cl- for negatively charged bile acids; bound bile lost in feces

2. decrease in bile acids returning to liver decreases sterol pool -- induced synth of HMG and LPL receptors

3. Plasma LDL falls via increased LDL receptor expression, but production of bile acids is restored via HMG

4. Fall in plasma LDL is limited by increase in hepatic cholesterol synth

5. Bile acid-binding resins do NOT lower plasma cholesterol in genetic absence of LDL receptors

Primary effect is decrease LDL
Combined resin treatments?
resin = LDL decrease by 10-35%

Addition of statin causes further fall in LDL of 25% to give total decrease LDL by about 50%

resin + statin + niacin - 70% LDL decrease
resin therapeutic indication?
used to lower LDL in patients at risk -- same group as statins
resin toxicity?
1. GI - constipation, abdominal bloating and pain

2. May bind other drugs in GI tract and prevent their absorption
-- warfarin, propanolanol, tetracyclines, furosemide, HCTZ, pravastatin, fluvastatin, thyroxine
-- take other drugs one hour before or 4h after p.o. dosing w/ a resin

3. COLSEVELAN does NOT affect F of digoxin, lovastatin, atorvastatin, simvastatin, and warfarin

4. CHOLESTYRAMINE = pregnancy category C and COLESEVELAN = category B
NOT a first line drug

Water-soluble B complex vitamin = vit B3

No prescription needed, but doses of 3-6g/day needed
Niacin MOA?

1. decreases plasma free f.a. via inhib lipolysis in adpocytes; decrease free f.a. decreases hepatic synth of TGs

2. decrease in plasma VLDL results from:
-- decrease TG synth
-- increased VLDL clearance via activation LPL

3. Plasma LDL and Tc fall as result of decrease in plasma VLDL

4. Increases plasma HDL conc via decrease rate catabolism of ApoA-I
-- HDL response depends on initial value HDL
-- [HDL]< 30mg/dl, then increase HDL is only 5-10mg/dl
-- [HDL]> 30mg/dl, then increase may be as large as 20-30mg/dl
Niacin therapeutic indications?
1. primarily as adjunctive therapy b/c of high frequency of S/Es

2. used to treat patients w/ elevated TGs and low HDL (dyslipidemias)

3. Used to lower TGs, VLDL, LDL, and raise HDL in patients w/ mixed hyperlipidemias (increased Tc and TGs)
Niacin toxicity?
1. flushing and pruritis in face and upper body common, but symptoms decrease by 75% after 1-2wks therapy; flushing decreased by tx w/ 1 ASA/day

2. GI - n/v/d and dyspepsia

3. Dry skin

4. Increased plasma AST and ALT; often remints if dose decreased

5. Increased plasma glucose conc or decreased glucose tolerance in patients w/ subclinical DMII

6. Symptoms of gout from increased plasma uric acic conc

7. Contraind in pts w/ ulcer disease or DMII

8. Extended release niacin still causes flushing

9. INOSITOL HEXANICOTINATE is a new formulation that does NOT cause flushing or puritis
Gemfibrozil use, MOA?
**Used to treat Hyperglyceridemia

Activates LPL, espec in skeletal muscle
-- increased hydrolysis VLDL increases plasma IDL which is cleared by liver
-- less IDL means less LDL
-- increased IDL may INCREASE plasma LDL if liver does not clear increaseed IDL
Gemfibrozil therapeutic indications?
1. used to treat patients with hypertriglyceridemia who are at risk for pancreatitis

2. Used as single agent to lower TGs and increase HDL

3. Used to lower VLDL and TGs, and raise HDL in patients being treated w/ statin

4. Type II DM -- lower their TGs which will make their LDLs bigger, thus less atherogenic
Gemfibrozil toxicity?
1. GI discomfort

2. Myopathy - myositis flu-like syndrome w/ elevated CPK

3. Increased risk gallstones

4. Avoid in patients w/ renal/hepatic disease
chemically related to gemfibrozil and has same indications, MOA, pharm effects, and toxicity as gemfibrozil