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Therapeutics 2 - Exam 5 > anti-hyperlipidemia > Flashcards

anti-hyperlipidemia Flashcards

hockerman

1
Q

what is the role of cholesterol?

A

essential component of cell membranes
precursor to sterols and steroids

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2
Q

what is the role of TGs?

A

storage form of fuel to support generation of high energy compounds
component of structural lipids

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3
Q

what is a lipoprotein?

A

spherical macromolecular aggregate
trasports cholesterol and TG in the blood

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4
Q

what is the composition of lipoprotein surface?

A

phospholipid, free cholesterol, and protein (apoprotein)

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5
Q

what is the composition of a lipoprotein core?

A

TG
cholesterol ester

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6
Q

what is the function of apoproteins?

A

regulate transport and metabolism

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7
Q

what is the purpose of the lipoprotein lipase system?

A

release free fatty acids from lipoproteins

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8
Q

what are the major classes of lipoproteins?

A

chylomicrons
VLDL
IDL
LDL
HDL

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9
Q

what is a chylomicron?

A

lipoprotein involved in the transport of dietary lipids from the gut to liver and adipose tissue

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10
Q

what is a VLDL?

A

very low density lipoprotein
secreted by liver into blood as a source of TGs

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11
Q

what is a IDL?

A

an intermediate density lipoprotein that is basically just TG-depleted VLDL

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12
Q

what is a LDL?

A

low density lipoprotein
main cholesterol form in the blood

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13
Q

what is a HDL?

A

high density lipoprotein
secreted by liver
acquires cholesterol from peripheral tissues and atheromas
reverse cholesterol transport

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14
Q

what is the largest lipoprotein?

A

chylomicrons

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15
Q

what lipoprotein has the highest TG content?

A

chylomicrons

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16
Q

what lipoprotein is the smallest?

A

HDLs

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17
Q

what lipoprotein has the highest protein content?

A

HDL

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18
Q

what is ApoA-I?

A

structural apolipoprotein in HDL and ligand of the ABCA1 receptor
mediates reverse cholesterol transport

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19
Q

where is ApoA-I production location?

A

liver and intestine

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20
Q

what is ApoB-100?

A

structural apolipoprotein in VLDL, IDL, and LDL
LDL receptor ligand

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21
Q

where is ApoB-100 production located?

A

liver

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22
Q

what is ApoB-48?

A

structural apolipoprotein in chylomicrons

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23
Q

where is ApoB-48 production located?

A

intestine

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24
Q

what is ApoE?

A

apoplipoprotein that is a ligand for LDL remnant receptor
mediates reverse cholesterol transport with HDL

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25
Q

where is ApoE production located?

A

liver and other tissues?

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26
Q

What is ApoCII?

A

apolipoprotein that binds to lipoprotein lipase to enhance TG hydrolysis

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27
Q

what is the location of ApoCII?

A

chylomicrons and VLDL

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28
Q

what is hepatic lipase?

A

enzyme produced in the liver that degrades the TG in IDL to form LDL

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29
Q

what is lipoprotein lipase (LPL)?

A

enzyme found in capillaries of fat, cardiac muscle, and skeletal muscle
breaks down TGs into free FA and glycerol

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30
Q

what is lecithin-cholesterol acyltransferase (LCAT)?

A

enzyme on LDL and HDL
esterfies free cholesterol to form cholesterol esters for HDL transport

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31
Q

what is cholesterol ester transfer protein (CETP)?

A

protein in HDL
allows HDL to transfer cholesterol esters to other lipoproteins in exchange for TGs

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32
Q

what is the major source of cholesterol?

A

liver synthesis

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33
Q

what ratio is associated with an increased risk of CVD?

A

greater than 4.5 of total cholesterol to HDL

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34
Q

what are the diseases associated with hyperlipoproteinemia?

A

atherosclerosis
premature coronary artery disease
stroke
(neurologic disease)

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35
Q

what are the diseases associated with hyperTGemia?

A

pancreatitis
xanthomas (raised, waxy skin lesions)
increased risk of CHD

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36
Q

what is atherosclerosis?

A

excess accumulation of cholesterol in the form of LDL in vascular smooth muscle which causes accumulated plaques

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37
Q

what are the goals of therapy for hyperlipidemia?

A

reduce reabsorption of excreted bile acids
decrease secretion of VLDL from liver
decrease synthesis of cholesterol
increase liver LDL receptor number
increase hydrolysis of lipoprotein TG

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38
Q

what is % reduction in incidence of CHD compared to reduction in cholesterol levels?

A

for every 10% reduce in cholesterol levels, theres a 10-30% reduction in CHD risk

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39
Q

what are the drug classes that target high cholesterol?

A

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

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40
Q

what are drugs that target high TGs?

A

fibrates
niacin
omega 3 FA

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41
Q

what is MOA of BARs?

A

inhibit reabsorption of bile acids from intestine
done by binding bile acids to form insoluble complex excreted in feces
up regulate LDL receptors in liver

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42
Q

what is the structure of BARs?

A

large molecular weight polymers (resins) that exchange chloride ion for bile acids

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43
Q

what drugs are BARs?

A

cholestyramine (questran)
colestipol (colestid)

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43
Q

what is the % reduction in LDL for BARs?

A

20%
but may increase HDL and TG

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43
Q

what is the indication of BARs?

A

primary hypercholesterolemia

43
Q

what are counseling points of BARs?

A

take before meals
high fiber diet and water helps resolve side effects

44
Q

what are the SE of BARs?

A

constipation
bloating

45
Q

what drugs absorptions are influenced by BARs?

A

acetaminophen
zetia
thiazides
warfarin
digoxin
fibrates
OCs
corticosteroids
TZDs

46
Q

what is zetia?

A

cholesterol and phytosterol absorption inhibitor that inhibits NPC1L1

47
Q

what is NPC1L1

A

neimann-pickC1-like1
transporter expressed on apical surface of enterocytes in the small intestine
moves free FA from the lumen of the gut or bile into enterocytes of hepatocytes

48
Q

what is the indication of zetia?

A

reduction of LDL levels used in combination with statins

49
Q

what is % reduction in LDL levels of taking zetia?

A

17%
enhances statin action up to 20%

50
Q

what are the SE of zetia?

A

generally well-tolerated with a low incidence of liver/skeletal muscle damage

51
Q

what drugs are HMG-CoA reductase inhibitors?

A

fluvastatin (lescol)
rosuvastatin (crestor)
atorvastatin (lipitor)
lovastatin (mevacor)
simvastatin (zocor)
pravastatin (pravachol)
pitavastatin (livalo)

52
Q

what statins are prodrugs?

A

lovastatin
simvastatin

53
Q

what is the MOA of statins?

A

competitively inhibits HMG-CoA reductase
up-regulates LDL receptors
enables more LDL to be delivered to liver thus reducing cholesterol

54
Q

what about statins structure is relavant?

A

they are structurally similar to HMG-CoA

55
Q

what is HMG-CoA reductase?

A

rate-limiting enzyme in cholesterol biosynthesis

56
Q

what is SREBP?

A

sterol regulatory element binding protein
transcription factor that up-regulates the expression of gene encoding the LDL receptor

57
Q

what is SCAP?

A

SREBP cleavage activating protein
binds cholesterol and acts as a sterol sensor

58
Q

what is the indication of statins?

A

hypercholesterolemia (elevated LDL with slightly elevated TGs)
used immediately after an MI regardless of lipid levels

59
Q

what is the % in LDL, TG, and HDL due to statins?

A

20-60% reduction in LDL
10-33% reduction in TG
5-10% increase in HDL

60
Q

when should short half-life statins be administered?

A

in the evening to inhibit nocturnal cholesterol synthesis

61
Q

what statins have short half-lives?

A

IR fluvastatin
IR lovastatin
simvastatin

62
Q

what statins are metabolized by CYP3A4?

A

lovastatin
simvastatin
atorvastatin

63
Q

what drugs interact with statin and CYP3A4?

A

macrolide antibiotics
cyclosporine
ketoconazole
grape fruit juice

64
Q

how competing CYP3A4 drugs interact with statins?

A

cause statins to accumulate

65
Q

what statins are metabolized by CYP2C9?

A

fluvastatin
rosuvastatin

66
Q

what drugs are CYP2C9 inhibitors that interact with statins?

A

cimetidine
metronidazole
amiodarone

67
Q

how does CYP2C9 inhibitors interact with statins?

A

increasing plasma levels of statins

68
Q

what is the metabolism of pravastatin?

A

sulfation
most excreted unchanged

69
Q

what is the metabolism of pitavastatin?

A

enterohepatic recirculation
most excreted unchanged in bile

70
Q

what is the SE of statins?

A

skeletal muscle effects with renal dysfunction
myoglobinuria
hepatotoxicity
increased incidence of T2DM

71
Q

what should be monitored with statins

A

serum creatine phosphokinase (CPK) and serum transaminase activity

72
Q

when is the incidence of rhabdomyolysis increased?

A

co-administration of statin and CYP inhibitors or gemfibrozil

73
Q

what drugs are used adjacent to statins?

A

bempedoic acid
PCSK9 inhibitors

74
Q

what is bempedoic acid?

A

nexletol
ACL inhibitor that reduces serum LDL and total cholesterol levels when added to statin therapy
used in patients with heterozygous familial hypercholesterolemia (HeFH) or established ASCVD

75
Q

what is ACL?

A

ATP-citrate lyase inhibitor
enzyme upstream of HMG-CoA reductase in the cholesterol synthetic pathway

76
Q

what is SE of bempedoic acid?

A

hyperuricemia
gout –> due to OAT2 inhibition in renal tubules

77
Q

what is the metabolism of bempedoic acid?

A

metabolized by glucuronidation and excreted via kidneys

78
Q

what is half life of bempedoic acid?

A

21 hours (so take 1QD PO)

79
Q

what is PCSK9?

A

proprotein convertase subtilisin kexin type 9
serin protease that promotes degradation of LDL receptors in the liver

80
Q

what drugs are PCSK9 inhibitors?

A

alirocumab (praluent)
evolocumab (repatha)
inclisiran (leqvio)

81
Q

how do praluent and repatha function?

A

human IgG antibodies against PCSK9
increase LDL-R number and reduce serum LDL-C levels

82
Q

what is the indication of praluent and repatha?

A

adjunct to diet and maximally tolerated statin therapy in patients with established ASCVD, HeFH, and HoFH

83
Q

what is inclisiran?

A

siRNA
hybridizes PCSK9 mRNA
directs degradation in hepatocytes
lowers LDL cholesterol

84
Q

what is the indication of inclisiran?

A

adjunct to statins in HeFH and ASCVD

85
Q

what is SE of inclisiran?

A

injection site reaction
arthralgia

86
Q

what drugs are used to lower serum cholesterol in patients with HoFH?

A

juxtapid (lomitapide)
mipomersen (kynamro)
evinacumab (evkeeza)

87
Q

what is juxtapid?

A

lomitapide
MTTP inhibitor that inhibits the assembly of ApoB containing lipoproteins in the liver and intestine

88
Q

what is the indication of juxtapid?

A

adjunct to other treatments in patients with HoFH

89
Q

what is the SE of juxtapid?

A

risk of liver damage

90
Q

what is the indication of mipomersen?

A

adjunct to other treatments for patients with HoFH

91
Q

what is the SE of mipomersen?

A

risk of liver damage
risk of hepatic steatosis

92
Q

what is evinacumab?

A

evkeeza
antibody that increases LPL and endothelial lipase (EL) activity
through preventing ANGPTL3 mediated inhibition
lowers LDL cholesterol

93
Q

what is the indication of evinacumab?

A

treatment of HoFH

94
Q

what are fibric acid derivatives?

A

molecules that bind to PPAR-a
regulate gene transcription along with the retinoic acid receptor (RXR)

95
Q

what drugs are fibric acid derivatives?

A

clofibrate
gemfibrozil
fenofibrate
ciprofibrate
bezafibrate

96
Q

what is the % changes of LDL, TGs, and HDLs due to fibric acid derivatives?

A

6-20% reduction in serum LDL
35-53% reduction in serum TGs
15-30% elevation of HDL

97
Q

what are the indications of fibric acid derivatives?

A

hypertriglyceridemia with predominant VLDL and second-line for mixed hyperlipidemia

98
Q

what are the SE of fibric acid derivatives?

A

gallstones
rhabdomyolysis
use in caution with statins

99
Q

what is the main drug-drug interaction of fibric acid derivatives?

A

potentiate warfarin effects

100
Q

what is niacin?

A

vit B3 (nicotinic acid)
can lower serum lipids at high doses (1-3g/day)

101
Q

what are changes that occur in lipids due to niacin?

A

reduce serum TGs
increase LPL activity –> increase clearance of VLDL
decrease hepatic VLDL production
may significantly reduce serum LDL and TGs
increase HDL levels

102
Q

what are the targets of niacin?

A

adipose tissue
liver
macrophages

103
Q

what is the MOA of niacin in adipose tissue?

A

inhibits TG lipolysis by hormone-sensitive lipase via activation of GPR109A
decreases FA transport to liver

104
Q

what is the MOA of niacin in liver?

A

inhibits FA synthesis and esterification –> reducing TG export via VLDL
reduces clearance of apoA-I but not CE –> increasing HDL levels and reverse transport

105
Q

what is the MOA of niacin in macrophages?

A

increase expression of CD36 and ABCA1
decreases the CE content via HDL-mediated reverse transport

106
Q

what is the indication of niacin?

A

mixed hyperlipidemias
hyperTGemia by 25-30% with risk of pancreatitis
raising HDL levels by 15-35%
in combination with resin drugs or statins to treat hyperlipidemia

107
Q

what is the SE of niacin?

A

marked vasodilation (cutaneous flushing)
itching
tingling of upper body
headache
hepatotoxicity

108
Q

what mediates the initial SE of niacin?

A

prostaglandins
treat with ibuprofen or aspirin

Therapeutics 2 - Exam 5 (14 decks)

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