Anti-Hyperlipidemic Drugs

Question 1

Major lipids

Answer 1

cholesterol: essential component of cell membranes; precursor to sterols and steroids
triglyceride: storage form of fuel to support generation of high energy compounds; component of structural lipids
both are transported in blood in macromolecular aggregates known as lipoproteins

Question 2

Know the relative size, composition, and physiological function of the major classes of lipoproteins

Answer 2

lipids form lipoproteins to help them move around the body
lipoproteins transport cholesterol & triglycerides in blood; spherical particles with phospholipid, free cholesterol & protein making up surface; core made up of triglyceride & cholesterol ester; apoproteins on surface are critical in regulating transport & metabolism; lipoprotein lipase system releases free FAs from lipoproteins
major classes of lipoproteins: chylomicrons, VLDL, IDL, LDL, HDL
classes based on density, composition, and electrophoretic mobility

Question 3

Chylomicrons

Answer 3

involved in transport of dietary lipids from gut to liver and adipose tissue
dumped into lymphatic system and makes its way through the body

Question 4

VLDL - very low density lipoprotein

Answer 4

secreted by liver into blood as a source of triglycerides

Question 5

IDL - intermediate density lipoprotein

Answer 5

triglyceride-depleted VLDLs

Question 6

LDL - low density lipoprotein

Answer 6

main cholesterol form in blood

Question 7

HDL - high density lipoprotein

Answer 7

secreted by liver and acquire cholesterol from peripheral tissue and atheromas (reverse cholesterol transport)
bring cholesterol from peripheral tissues and back into liver

Question 8

Lipoproteins sizes

Answer 8

bigger they are –> less dense they are
biggest: chylomicron –> VLDL –> LDL –> HDL

Question 9

Lipoproteins compositions

Answer 9

chylomicrons: mostly triglycerides
VLDL: mostly triglycerides, more cholesterol too
LDL: more cholesterol relative to TGs
HDL: mostly protein

Question 10

Important apolipoproteins

Answer 10

ApoA-I
ApoB-100
ApoB-48
ApoE
ApoCII

Question 11

ApoA-I

Answer 11

structural in HDL; ligand of ABCA1 receptor mediates reverse cholesterol transport produced in liver and intestine

Question 12

ApoB-100

Answer 12

structural in VLDL, IDL, LDL; LDL receptor ligand produced in liver

Question 13

ApoB-48

Answer 13

structural in chylomicrons produced in intestine

Question 14

ApoE

Answer 14

ligand for LDL remnant receptor reverse cholesterol transport with HDL; produced in liver and other tissues; helps get cholesterol back into the liver

Question 15

ApoCII

Answer 15

found in chylomicrons, VLDL; binds to lipoprotein lipase to enhance TG hydrolysis

Question 16

Know the exogenous and endogenous pathways for lipid absorption and transport

Answer 16

LDL-lipoprotein lipase: in capillaries of fat, cardiac & skeletal muscle
HL-hepatic lipase: produced in liver, key in converting IDL to LDL
CETP-cholesterol ester transfer protain: more cholesterol esters from HDLs into IDLs in exchange for trigylcerides

Question 17

Endogenous pathway

Answer 17

liver secretes VLDL –> IDL –> LDL –> cholesterol distributed throughout the body

Question 18

Exogenous pathway

Answer 18

dietary fat + cholesterol –> intestine –> chylomicrons –> chylomicron remnants –> liver

Question 19

Know the role of the LDL receptor in lipid metabolism, and factors that regulate LDL receptor levels

Answer 19

LDL goes in through LDL receptors –> lipoproteins taken into lysosome
mLDL goes in through CD36 or SR-A –> lipoproteins taken into lysosome
fate 1: cholesterol is esterified, now have long chain FA (storage form)
fate 2: free cholesterol effluxed, HDL stimulates this
CEH = cholesterol ester hydrolase, hydrolyzes cholesterol ester back to free cholesterol

Question 20

Understand the central role of the liver in cholesterol synthesis and lipid distribution

Answer 20

De novo synthesis is the major source of cholesterol
liver synthesis is most critical to total body burden
mevalonate is the key building block for cholesterol

Question 21

Lipoprotein disorders

Answer 21

detected by measuring lipid in serum after a 10 hr fast
ratio of total cholesterol to HDL-cholesterol is key in assessing risk of CVD
ratio > 4.5 is associated with increased risk of CVD
ratio of </= 3.5 is desirable, ratio of < 3 is optimal

Question 22

Give the diseases that are associated with hyperlipoproteinemia and hypertryglyceridemia

Answer 22

hyperlipoproteinemia: atherosclerosis - excess accumulation of cholesterol in vascular smooth muscle, premature coronary artery disease, neurologic disease - stroke
hypertriglyceridemia: pancreatitis, xanthomas, increased risk of CHD

Question 23

Atherosclerosis

Answer 23

fatty streak - initial stage, leads to accumulated plaques, reduces blood flow
LDL receptors are present on endothelial cells
monocyte squeezes in b/w endothelium, gets into intima –> oxidized (modified) LDL gets into initma and stimulates T cell sectretion –> T cells secrease # of pro-inflammatory cytokines with chemotactic effect on monocytes –> causes differentiation of monocytes into macrophages –> macrophage starts to take up LDL –> store as cholesterol esters –> forms foam cells –> cell dies

Question 24

Know the strategies for controlling hyperlipidemias and give the molecular targets, mechanism of action, and major side-effects for: statins, bile acid sequestrants, ezetimibe, bempedoic acid fibrates, niacin, omega-3 fatty acids

Answer 24

goals of therapy: prevent formation of atherosclerotic plaques; decrease reabsorption of excreted bile acid; decrease secretion of VLDL from liver; decrease synthesis of cholesterol; increase hydrolysis of lipoprotein triglycerides
each 10% reduction in cholesterol levels is associated with 10-30% reduction in incidence of coronary heart disease

Question 25

Drugs mainly for high cholesterol

Answer 25

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

Question 26

Drugs mainly for high triglycerides

Answer 26

fibrates niacin omega-3 fatty acids

Question 27

Strategies for controlling hyperlipidemia

Answer 27

statins - inhibit HMG CoA reductase fibrates, niacin, omega-3 FAs - lipoprotein catabolism bile acid sequestrants - inhibit reabsorption of cholesterol ezetimibe - inhibits diet cholesterol

Question 28

Bile acid-binding resins

Answer 28

MOA: inhibits reabsorption of bile acids from intestine by binding bile acids to form insoluble complex excreted in feces; exchanging bile acid for chloride; want to interfere with the recycling and make the liver use more cholesterol to make bile acids, get more cholesterol, bring LDLs back into liver and prevent going into peripheral tissues up-regulate LDL receptors in liver when liver's running low on cholesterol ex: cholestyramine and colestipol - polymers with (+) charge, exchange counterion chloride) for bile acids cholesterol oxidized by CYP450s to cholic acid - negatively charges, will bind to the (+) charged resins

Question 29

Bile acid binding resins SEs

Answer 29

constipation and bloating

Question 30

Bile acid binding resins drug interactions

Answer 30

acetaminophen, thiazides, warfarin, digoxin, fibrates, ezetimibe, oral contraceptive, corticosteroids, thiazolidinediones

Question 31

Ezetimibe

Answer 31

cholesterol absorption inhibitor; inhibits intestinal absorption of phyosterols and cholesterol MOA: inhibits intestinal absorption of cholesterol from dietary sources and reabsorption of cholesterol excreted in bile (inhibits NPC1L1 - Neimann-Pick C1-like 1, ezetimibe binds to this transporter)

Question 32

NPC1L1 - cholesterol transporter

Answer 32

expressed on apical surface of enterocytes in small intestine cholesterol activates sterile sensing domain (SSD) which stimulates endocytosis, brings in cholesterol that's bound in the membrane around the transporter ezetimibe blocks this transporter

Question 33

Ezetimibe SEs

Answer 33

low incidence of liver/skeletal muscle damage

Question 34

Recognize the molecular structure of statins and indicate which statins are prodrugs

Answer 34

HMG-CoA reductase inhibitors - "statins" statins are derivatives of mevalonic acid lovastatin and simvastatin are prodrugs

Question 35

HMG-CoA reductase inhibitors

Answer 35

MOA: competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis up-regulate LDL receptors enabling more LDL delivered to liver, thus reducing plasma cholesterol prevent conversion of HMG-CoA to mevalonic acid

Question 36

Mechanism for upregulation of hepatic LDL receptors by statins

Answer 36

reducing synthesis of cholesterol in the liver, causes the liver to react, allows it to take more LDL up from plasma SREBP - sterol regulatory element binding protein has 2 domains - regulatory and basic helix loop helix domain; this complex stays when sterols are present; SCAP - SREBP cleavage activating protein keeps it in the ER when a lot of sterols are around when sterols depleted by inhibiting HMG-CoA reductase --> site one protease (S1P) cleaves SREBP, site two protease cleaves bHLH from transmembrane domain --> complex translates to golgi apparatus --> goes to nucleus to activate transcription --> transcription + production of LDLr --> incrase hepatic LDL uptake

Question 37

HMG-CoA reductase inhibitors metabolism

Answer 37

CYP3A4: lovastatin, simvastatin and atorvastatin - tend to accumulate in presence of drugs that inhibit or compete for CYP 3A4: macrolide antibiotics, cyclosporine, ketoconazole, grapefruit juice CYP 2C9: fluvastatin, rosuvastatin - inhibitors may increase plasma levels: cimetidine, metronidazole, amiodarone sulfation: pravastatin, most excreted unchanged pitavastatin excreted unchanged in bile, undergoes enterohepatic recirculation

Question 38

HMG-CoA reductase inhibitors SEs

Answer 38

skeletal muscle effects: rhabdomyolysis with renal dysfunction secondary to myoglobinuria, monitor creatine phosphokinase; increased incidence when co-adm with CYP inhibitors, gemfibrozil hepatotoxicity - monitor serum transaminase activity increased incidence of T2DM

Question 39

ATP-citrate lyase inhibitor

Answer 39

bempedoic acid (nexletol) adjunct to statins inhibits OAT2 in renal tubules - inhibits secretion of uric acid

Question 40

Bempedoic acid SEs

Answer 40

hyperuricemia and gout

Question 41

Drugs used to lower serum cholesterol in pts with homozygous familial hypercholesterolemia

Answer 41

LDL-r function is severely reduced in this condition lomitapide mipomersen angiopoietin-like protein 3

Question 42

Recognize the molecular structure of fibrates and indicate which fibrate is a prodrug

Answer 42

fibric acid derivatives: peroxisome proliferator-activated receptor-alpha activators (PPARalpha) fenofibrate must undergo bioactivation to fenofibric acid gemfibrozil

Question 43

Fibrates

Answer 43

bind to PPAR-alpha and regulate gene transcription along with the retinoic acid receptor (RXR) to reduce triglyceride levels

Question 44

Fibrates SEs

Answer 44

gallstones (cholelithiasis) skeletal muscle effects - rhabdomyolysis drug interaction: potentiate the effects of warfarin

Question 45

Niacin MOA

Answer 45

reduces serum triglycerides blocks the mobilization of FFAs from adipose tissue, so less FFAs are taken to the liverm less TG synthesis, less VLDL export, decrease LDL, increase HDL increases lipase activity to increase clearance of VLDL --> decreases hepatic VLDL production --> may significantly reduce serum LDL and TG --> increases HDL levels niacin inhibits a hormone-sensitive lipase in adipose tissue which reduces the breakdown of triglycerides to free fatty acids, and the transport of free fatty acids to the liver. the reduction in transport of free fatty acids from fat to liver decreases hepatic triglyceride synthesis the reduction in hepatic triglyceride synthesis inhibits VLDL secretion from hepatocytes, which in turn decreases the production of LDL.

Question 46

Niacin targets

Answer 46

adipose tissue: inhibits TG lipolysis by hormone-sensitive lipase - decreasing FA transport to liver via activation of GPR109A liver: inhibits FA synthesis and esterification reducing TG export via VLDL - reduces clearance of ApoA-I but not CEs, increasing HDL levels and reverse transport macrophages: increases expression of CD36 and ABCA1, decreasing CE content via HDL-mediated reverse transport

Question 47

Niacin SEs

Answer 47

marked vasodilation (flushing), itching, tingling of upper body and headache - prostaglandins mediate these, treat with aspirin or ibuprofen hepatotoxicity

Question 48

Omega-3 fatty acid ethyl esters

Answer 48

nutrients combo of ethyl esters of omega-3 fatty acids lovaza, omtryg, vascepa MOA: reduce serum triglycerides; reduce synthesis of triglyceride in liver: omega-3 FAs are poor substrates for enzymes responsible for TG synthesis; inhibit esterification of other FAs

Question 49

Omega-3 FAs SEs

Answer 49

can increase LDLc levels, not EPA-ethyl ester alone combined with statins to reduce LDLc level

Question 50

Eicosapentaenoic acid (an omega-3 FA)

Answer 50

TXA3- less potent in stimulating platelet aggregation than TXA2; PGI3 - equipotent in ihibiting platelet aggregation than PGI2 low incidence of atherosclerotic disease with a tendency to bleed inhibiting platelet aggregation that would normally be mediated by TXA2, still maintaining good prostacyclin activity even if you incorporate this FA into the synthetic pathway

Question 51

Explain the mechanism of action of angiopoietin-like protein 3 inhibitors

Answer 51

reduce LDL levels independently of LDLrs - mechanism does not require LDL-R evinacumab (evkeeza): monoclonal antibody increases lipoprotein lipase and endothelial lipase activity by preventing ANGPTL3 mediated inhibition, this binding interferes with the ANGPTL3 ability to inhibit activity of LPL and EL; lowers LDLc evinacumab allows greater breakdown by LPL and EL, by allowing greater breakdown of TGs by these lipases from the VLDL, the IDL that results is more likely to be cleared by the remnant receptor as an IDL than to be processed to an LDL (reduce conversion of IDL to LDL)

Question 52

Explain the mechanism of action of mipomerson and lomitapide, and their primary toxicities

Answer 52

lomitapide and mipomerson - inhibits apo B lipoprotein synthesis

Question 53

Lomitapide

Answer 53

juxtapid small molecule microsomal TG transfer protein (MTTP) inhibitor inhibits assembly of Apo B containing lipoproteins in liver + intestine - interferes with assembly of both VLDL and chylomicrons high risk of liver damage

Question 54

Lomitapide MOA

Answer 54

mechanism does not require LDL-R MTTP inhibitors inhibit VLDL assembly and reduce VLDL secretion into bloodstream from liver small molecule inhibits microsomal triglyceride transport protein (MTTP); also works in the intestines - interferes with packaging of chylomicrons affect ability to absorb lipophilic compounds

Question 55

Mipomersen

Answer 55

kynamro phosphorothioate anti-sense oligonucleotide inhibitor of Apo B100, more specific to ApoB100, greater effect on VLDL export hybridizes Apo B100 mRNA in liver and promotes degradation binds to Apo B100 mRNA and causes it to be destroyed; duplex mRNA w/ oligo, mRNA will be degraded --> degrading Apo B100 mRNA reduces Apo B100 protein, reduce VLDL export VLDL are processed LDL, so reducing VLDL export will reduce these serum LDL cholesterol as well phosphorothioate has an added sulfur instead of oxygen, decreases ability of nucleases to degrade this oligo high risk of liver damage

Question 56

Explain the mechanism of action of the PCSK9 inhibitors

Answer 56

augment the clearance of LDL cholesterol PCSK9 - proprotein convertase subtilisin kexin type 9 (serine protease) - promotes degradation of LDL receptors in liver MOA: controls level of LDLr on surface of hepatocytes --> binds to LDLr and marks it for internalization + degradation; develop antibody against PCSK9 that will bind this soluble enzyme, prevent it from binding LDLr allowing recycling of receptor when internalized alirocumab and evolocumab are human IgG Abs against PCSK9 - increase LDLr # and reduce serum LDLc levels inclisiran: siRNA hybridizes PCSK9 mRNA and directs degradation of PCSK9 mRNA in hepatocytes, lowers LDLc

Question 57

PCSK9 inhibitors SEs

Answer 57

injection site rxn arthralgia