atherosclerosis

Question 1

cholesterol

Answer 1

• essential component of animal cell membranes, allows fluidity
• dietary sources: animal fats; cholesterol biosynthetic p/way (25% total cholesterol production occurs in the liver)

Question 2

HMG CoA Reductase

Answer 2

converts HMG CoA to Mevalonic Acid, essential for cholesterol synthesis

Question 3

triglycerides

Answer 3

ester

• glycerol & fatty acids
• one of the main components in animal fat and vegetable oils
• store and circulate fat

Question 4

lipoproteins

Answer 4

complex of lipids and PRO, hydrophobic core w cholesteryl esters and triglycerides

• unesterified cholesterol, phospholipids, apoproteins at membrane
• enable transport of lipids, TG, cholesterol
• PRO components of lipoproteins are called apolipoproteins

Question 5

exogenous lipid metabolism

Answer 5

1. absorption of dietary cholesterol and FA
2. in intestinal cell: FFA combine with glycerol to form TG; cholesterol esterified to form cholesterol esters via ACAT; TG and cholesterol are assembed into chylomicrons
3. enter circulation
4. lipoprotein lipase removes TG in extrahepatic tissues, remnants taken up by hepatocytes

Question 6

Apolipoproteins on HDL

Answer 6

A1, AII, C, E, D (more dense)

Question 7

Apolipoproteins for LDL

Answer 7

b-100

Question 8

Apolipoproteins for IDL

Answer 8

b100, E, C

Question 9

VLDL Apolipoproteins

Answer 9

C, B100, E (less dense, increased diameter)

Question 10

chylomicron Apolipoproteins

Answer 10

B48, C, E, A1, AII

Question 11

ENDOgenous pway of cholesterol synthesis

Answer 11

Chylomicron remnants taken up by liver, converted to VLDL. VLDL (TG>CE) loses TG via lipoprotein lipase in tissues and becomes IDL (CE>TG). IDL can be converted to LDL by further removal of TG via hepatic lipase. LDL can be internalized in liver and non hepatic tissues. Liver converts to bile acids and secretes, non hepatic used for hormone prod, cell membrane synth, or stored. Enters macrophages and other tissues to form plaques. HDL formed from hepatic and intestinal synthesis of particles containing phospholipids and apolipoproteins, surface components from triglyceride depeleted chylomicron and VLDL remnants, aquisitiion of free chol from tissue sites and other lipoproteins. HDL converts to IDL if too much is produced.

Question 12

TG can be stored or _____

Answer 12

produce nutrients via liver

Question 13

Total cholesterol: desirable, borderline, high

Answer 13

240

Question 14

LDL: desirable, borderline, high

Answer 14

160

Question 15

HDL: high; desirable

Answer 15

> 60; men: > 40; women: >50

Question 16

triglycerides: desirable, borderline, high

Answer 16

200

Question 17

rx of borderline high hypercholesterolemia

Answer 17

dietary and lipoprotein analysis, possible drug therapy if CHD or 2 other risk factors (male, family history of CHD, smoker, HTN, low HDL, diabetes, obesity

Question 18

rx high hypercholesterolemia

Answer 18

1. dietary if no CHD or less than 2 risk factors

2. dietary & drug if CHD and 2 + risk factors

Question 19

rx very high hypercholesterolemia

Answer 19

(LDL > 190) dietary and drug.

Question 20

omega 3 fatty acids

Answer 20

activate PPARalpha, decreases triglycerides and may decrease LDL

• only those in fish oils, not from plant sources, are active
• avoid in pt with fish/shellfish allergies
• available OTC or as mixed omega 3 acid ethyl ester (lovaza), purified and chemically altered

Question 21

cholestyramine

Answer 21

• large polymeric cationic exchange resins, insoluble in H20
• safe and effective, but not appetizing (4-5 g 3-4x day)
• available as granular resins or tabs
• resins have to be taken w meals
• can effect vitamin absorption
• binds to and interacts with bile acids so they can’t be reabsorbed
• bind BA through ionic and hydrophobic interactions to prevent reabsorption
• increase uptke of LDL from upreg of LDL receptors
• increase hepatic prod of VLDL, increases TG by 15-20%

Question 22

colesevelam

Answer 22

• fewer SE
• can reduce hyperglycemia
• large polymeric cationic exchange resins, insoluble in H20
• safe and effective, but not appetizing (4-5 g 3-4x day)
• available as granular resins or tabs
• resins have to be taken w meals
• can effect vitamin absorption
• binds to and interacts with bile acids so they can’t be reabsorbed
• bind BA through ionic and hydrophobic interactions to prevent reabsorption
• increase uptke of LDL from upreg of LDL receptors
• increase hepatic prod of VLDL, increases TG by 15-20%

Question 23

CYP7A1

Answer 23

rate limiting enzyme to convert cholesterol to BA

Question 24

FGF 15/19

Answer 24

hormone that neg fb regulates CYP7A1

Question 25

SE of bile acid sequestrans

Answer 25

cholestyramine and colesevelam - dyspepsia, constipation, bloating diarrhea (reduced for colesevelam) - malabsoprtion of vitamin K (reduced for colesevelam) - impaired absoprtion of other drugs: digoxin, thyroxine, coumadin, thiazides, iron salts, pravastatin, fluvastatin, ezetimide, folic acid, aspirin, ascorbic acid. colesevelam does not bind digoxin, warfarin, or reductase inhibitors.

Question 26

niacin

Answer 26

water soluble vitamin incorporated into nicotinamide adenine dinucleotide (NAD) - inhibits VLDL secretion therefore ultimately decreases prod of LDL - decreases triglycerides more than cholesterol - no effect on bile production

Question 27

niacin SE

Answer 27

1) prostaglanding mediated cutaneous vasodilation: blunted w aspirin/ NSAID (flushed) 2. liver: reversible elevations in LFT, severe dysfunction reported with the use of OTC SR preps. not reported with ER prep. 3. long term niacin rx may increase insuline resistance 4. hyperuricemia: competes w uric acid for excretion by kidneys

Question 28

lovastatin

Answer 28

HMG CoA reductase inhibitors 1. competitively inhibit HMG CoA reductase 2. prodrug 3. decrease chol synthesis and upregulate LDL receptors and decrease LDL (really how decreases LDL) 4. marked first pass metabolism bc liver is the target organ, efficient 1st pass uptake may be more important than high bioavailability to achieve effect. 5. substrates of CYP3A4 6. taken in evening 7. absorption enhanced by food

Question 29

simvastatin

Answer 29

HMG CoA reductase inhibitors 1. competitively inhibit HMG CoA reductase 2. prodrug 3. decrease chol synthesis and upregulate LDL receptors and decrease LDL (really how decreases LDL) 4. marked first pass metabolism bc liver is the target organ, efficient 1st pass uptake may be more important than high bioavailability to achieve effect. 5. substrates of CYP3A4 6. taken in evening 7. absorption enhanced by food more effective

Question 30

pravastatin

Answer 30

HMG CoA reductase inhibitors 1. competitively inhibit HMG CoA reductase 2. active drug 3. decrease chol synthesis and upregulate LDL receptors and decrease LDL (really how decreases LDL) 4. marked first pass metabolism bc liver is the target organ, efficient 1st pass uptake may be more important than high bioavailability to achieve effect. 5. substrates of CYP 6. taken in evening 7. absorption enhanced by food

Question 31

fluvastatin

Answer 31

HMG CoA reductase inhibitors 1. competitively inhibit HMG CoA reductase 2. active drug 3. decrease chol synthesis and upregulate LDL receptors and decrease LDL (really how decreases LDL) 4. marked first pass metabolism bc liver is the target organ, efficient 1st pass uptake may be more important than high bioavailability to achieve effect. 5. substrates of CYP2C9 6. taken in evening 7. absorption enhanced by food less effective

Question 32

HMG CoA reductase inhibitors SE

Answer 32

lovastatin, simvastatin, pravastatin, fluvastatin - increases in LFT - increases in CK, myopathy, rarely rhabdomyolysis - worse w concurrent cyclosporin, clofibrate, niacin, erythromycin

Question 33

CYP3A4 interactions (lovastatin, simvastatin)

Answer 33

increased drug levels in presence of inhibitors: macrolides, cyclosprine, ketoconazole, fibrates, tacro, paroxetine; 1 L or more of grapefruit juice/day decreased in inducerts: phenytoin, barbs, rifampin

Question 34

CYP2C( interactions (fluvastatin)

Answer 34

increased in presense of inhibitors: ketoconazole, metronidazole, amiodarone

Question 35

all statins are metabolized by _____, interact with _______

Answer 35

glycosylation, gemfibrozil

Question 36

gemfibrozil

Answer 36

- serve as ligands for PPARalpha, which upregulates lipoprotein lipase, apo A1, apo A II (apo pros are major components of HDL and promote cholesterol efflux) - clears chylomicrons and VLDL quickly - lowers triglycerides (VLDL), raises HDL, modest decrease in LDL - primarily rx hyperglyceridemia (VLDL)

Question 37

clofibrate

Answer 37

- serve as ligands for PPARalpha, which upregulates lipoprotein lipase, apo A1, apo A II (apo pros are major components of HDL and promote cholesterol efflux - clears chylomicrons and VLDL quickly - lowers triglycerides (VLDL), raises HDL, modest decrease in LDL - primarily rx hyperglyceridemia (VLDL)

Question 38

fenofibrate

Answer 38

- serve as ligands for PPARalpha, which upregulates lipoprotein lipase, apo A1, apo A II (apo pros are major components of HDL and promote cholesterol efflux - clears chylomicrons and VLDL quickly - lowers triglycerides (VLDL), raises HDL, modest decrease in LDL - primarily rx hyperglyceridemia (VLDL)

Question 39

SE of fibric acids

Answer 39

fenofibrate, clofibrate, gemfibrozil -rashes, GI symp, arrythmias, low K, elevation in LFT -risk of myopathy increased when used in combo w statins (gemfibrozil increases concentration of most statins by inhibiting mech or glucuronidation of statin acid byproduct. fenofibrate does not use this p'way and has minimal effect on PK of statins) -increased risk of cholesterol gall stones

Question 40

ezetimibe

Answer 40

inhibitor of intestinal sterol absorption - impairs intestinal absorption of cholesterol by inhib NPC1L1 - absorbed and glucuronidated - excreted into bile and feces - not a CYP450 substrate

Question 41

drug therapy order for high LDL

Answer 41

1. bile acid sequestrans 2. nicotinic acid or HMG coA reductase inhibitor 3. combination

Question 42

drug therapy order for high LDL and TG

Answer 42

1. weight loss, alcohol restriction 2. nicotinic acid or gemfibrozil 3. bile acid sequestrants or HMG CoA reductatase inhibitors in combo with 2 above 4. combo of 2 of following: niacin, gemfibrozil, HMG coA reductase inhibitors. increased risk of toxicity

Question 43

drug therapy order for high TG

Answer 43

1. weight loss, ETOH restriction | 2. fibrate or nicotinic acid

Question 44

drug therapy order for low HDL

Answer 44

1. diet exercise, smoking cessation | 2. nicotinic acid or gemfibrozil