Dyslipidemia

Question 1

What are lipoprotein classes dependent on

Answer 1

density, composition, electrophoretic mobility

Question 2

What are the major classes of lipoproteins

Answer 2

chylomicrons, VLDL, IDL, LDL, HDL (very low, intermediate, low, high density lipoprotiens)

Question 3

LPL

Answer 3

lipoprotein lipase - in capillaries of fat, cardiac, skeletal muscle

Question 4

HL

Answer 4

hepatic lipase - produced in liver, key enzyme in converting IDL to LDL

Question 5

LCAT

Answer 5

Lethicin-cholesterol, acyltransferase - on LDL and HDL

Question 6

CETP

Answer 6

cholesterol ester transfer protein - in blood

Question 7

Liver synthesis of cholesterol

Answer 7

HMG-CoA synthase - HMG-CoA Reductase - mevalonate - IPP+DMAPP - GBB - FPP - FPP+ - Squalene - Lanosterol - Cholesterol

Question 8

Major source of cholesterol?

Answer 8

De novo synthesis - liver synthesis is most crucial to total body burden

Question 9

Hyperlipoproteinemia associated diseases

Answer 9

atherosclerosis, CAD, stroke

Question 10

hypertriglyceridemia associated diseases

Answer 10

pancreatitis, xanthomas, increased risk of CHD

Question 11

Foam cells

Answer 11

initiated by LDL accumulation - necrotic core of plaque = ACAT1 - acylCoA, CEH - cholesterol ester hydrolase

Question 12

Goals of hyperlipidemia therapy

Answer 12

decrease reabsorption of bile acids, secretion of VLDL from liver, synthesis of cholesterol. Increase liver LDL receptor #, hydrolysis of lipoprotein triglycerides

Question 13

Each 10% reduction in cholesterol levels is associated with

Answer 13

10-30% reduction in incidence of coronary heart disease

Question 14

Drugs for high cholesterol

Answer 14

bile acid binding resins, inhibitors of cholesterol absorption, inhibitors of cholesterol synthesis, PCSK9 inhibitors, MTTP inhibitors

Question 15

Drugs for high triglycerides

Answer 15

fibrates, niacin, omega-3 fatty acids

Question 16

Bile acid binding resins MOA

Answer 16

inhibit reabsorption of bile acids from intestines by binding bile acids to form insoluble complex excreted in feces, upregulate LDL receptors in liver

Question 17

Cholesterol absorption inhibitors MOA

Answer 17

Ezetimibe Inhibits NPC1L1 - Neimann-Pick C1-Like 1. inhibits intestinal absorption of cholesterol from diet and reabsorption of cholesterol excreted in bile

Question 18

HMG-CoA reductase inhibitors

Answer 18

Statins! mevalonic acid also

Question 19

Lovastatin and simvastatin are

Answer 19

Prodrugs! and lovastatin is isolated from aspergillus terreus

Question 20

HMG-CoA reductase inhibitors MOA

Answer 20

competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis.

Question 21

Mechanism for upregulating of hepatic LDL receptors by statins

Answer 21

SREBP - SCAP - S1P - S2P to increase LDLr and increase hepatic LDL uptake

Question 22

Statin indications

Answer 22

hypercholesterolemia, after MI irrespective of lipid levels

Question 23

Short half-life drugs are given

Answer 23

in the evening to inhibit nocturnal cholesterol synthesis

Question 24

Statins metabolized by CYP3A4

Answer 24

lovastatin, simvastatin, atorvastatin

Question 25

statins metabolized by CYP2C9

Answer 25

fluvastatin, rosuvastatin

Question 26

statin metabolized by sulfation

Answer 26

pravastatin - secreted mostly unchanged

Question 27

statin metabolized by enterohepatic recirculation

Answer 27

pitavastatin - main excreted unchanged in bile

Question 28

statin adverse effects

Answer 28

skeletal muscle effects - rhabdomyolysis, hepatotoxicity, increased incidence of T2DM

Question 29

ATP-citrate lyase inhibitor (ACL)

Answer 29

Bempedoic acid (Nexletol) - adjunct to statins. Reduces LDL and TC in pts with HeFH or ASCVD. May cause GOUT

Question 30

PCSK9 inhibitors

Answer 30

increase LDLR # and reduce serum LDL-C levels (PCSK9 promotes degradation of LDL receptors in liver)

Question 31

Inclisiran (Leqvio)

Answer 31

siRNA - hybridizes PCSK9 mRNA and directs degradation in hepatocytes, lowers LDLC in HeFH and ASCVD

Question 32

Drugs used is homozygous familial hypercholesterolemia

Answer 32

LDL-R function severely reduced

Question 33

Juxtapid (Lomitapide)

Answer 33

MTTP inhibitor - inhibits assembly of Apo B lipoproteins in liver and intestine (pts with homozygous - LDLR mutation - does not require LDLR!) high risk of liver damage

Question 34

Mipomersen (Kynamro)

Answer 34

Phosphorothioate anti-sense inhibitor of Apo B100 (pts with homozygous) high risk of liver damage - hepatic steatosis

Question 35

Evinacumab-dgnb (Evkeeza)

Answer 35

inhibits angiopoietin-like protein 3 in homozygous, doesnt require LDLR

Question 36

Fibric acid derivatives - gemfibrozil, fenofibrate (primarily reduces serum triglycerides)

Answer 36

peroxisome proliferator-activated receptor-alpha activators (PPARa). Fenofibrate must undergo bioactivation to fenofibric acid! Use caution with statins,

Question 37

Niacin

Answer 37

vitamin B3, nicotinic acid. reduces serum TG. Decreases FA transport to liver (adipose tissue). reduces TG export via VLDL, increases HDL and reverse transport (liver). Decreases CE content via HDL-mediated reverse transport (macrophages).

Question 38

Niacin indications and adverse effects

Answer 38

mixed hyperlipidemias, hypertriglyceridemia with risk of pancreatitis (decreases TG 25-30%) raises HDL 15-35%. Adverse effects: flushing, itching, headache - prostaglandins mediate, treat with aspirin, ibuprofen, hepatotoxicity in sustained-release

Question 39

Omega-3 fatty acids, lovaza, vascepa

Answer 39

EPA ethyl ester and DHA ethyl ester - indicated for severe hypertriglyceridemia. Reduce synthesis of TG in liver, inhibit esterification of other FA. can increase LDLc levels (not vascepa)