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Therapeutics 2 Exam 5 > Anti-Hyperlipidemic Drugs > Flashcards

Anti-Hyperlipidemic Drugs Flashcards

1
Q

What are the two major lipids that must be managed?

A

-Cholesterol

-Triglycerides
(triacylglycerol)

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2
Q

What is the precursor to sterols and steroids (and their structures)?

A

Cholesterol

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3
Q

What is the storage form of fuel used to support generation of high energy compounds?

A

Triglycerides

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4
Q

What are structural lipids made up of?

A

Triglycerides

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5
Q

What is the function of lipoproteins?

A

Transport BOTH cholesterol and triglycerides in the blood

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6
Q

Where is cholesterol synthesized?

A

Liver

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7
Q

What is the function of apoproteins?

A

Found on outside of lipoprotein surface

-Critical in regulating transport + metabolism (of lipoproteins)

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8
Q

What is the function of the Lipoprotein Lipase System?

A

Release free fatty acids from lipoproteins

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9
Q

What are the 3 defining characteristics of lipoprotein classes?

A

-Density
-Composition
-Electrophoretic Mobility

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10
Q

Arrange the classes of lipoproteins in order from biggest to smallest

A

Chylomicrons
VLDL
IDL
LDL
HDL

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11
Q

What is the function of chylomicrons?

A

-Lipoprotein

-Transports dietary lipids from gut to liver + adipose tissue

*Primarily transports triglycerides

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12
Q

What is the function of VLDL (Very Low Density Lipoprotein)?

A

-Secreted by the liver into blood

-Acts as source of triglycerides (lipids are packaged into VLDL)

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13
Q

What are IDLs (Intermediate Density Lipoproteins)?

A

Triglyceride-depleted VLDLs

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14
Q

What is the main form of cholesterol in the blood?

A

LDL (Low Density Lipoprotein)

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15
Q

What is the function of HDL (High Density Lipoprotein)?

A

-Secreted by liver

-Acquire cholesterol from peripheral tissue and atheromas

-Reverse cholesterol transport (bring back to liver)

*Mostly protein

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16
Q

Which lipoprotein is considered “Bad” cholesterol?

A

LDL (Low Density Liporprotein)

*main form of cholesterol in blood

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17
Q

Which lipoprotein is considered “Good” cholesterol?

A

HDL (High Density Lipoprotein)

*reverses cholesterol transport and brings cholesterol back to liver

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18
Q

Which lipoprotein is the apoprotein ApoA-I part of the structure of and what is its function?

A

-HDL

-Mediates reverse of cholesterol transport (brings back to liver)

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19
Q

Where is ApoA-I produced?

A

Liver AND Intestine

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20
Q

What receptor is ApoA-I the ligand of?

A

ABCA1 receptor

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21
Q

What lipoproteins is the apoprotein ApoB-100 present on?

A

VLDL
IDL
LDL

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22
Q

What receptor is ApoB-100 the ligand of?

A

LDL receptor

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23
Q

Where is ApoB-100 produced?

A

Liver

(VLDL, IDL, and LDL are all sources of lipids)

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24
Q

What lipoprotein is the apoprotein ApoB-48 present on?

A

Chylomicrons

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25
Q

Where is ApoB-48 produced?

A

Intestine

(chylomicrons transport dietary lipids from the gut)

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26
Q

What lipoprotein is ApoE present on and what is its function?

A

HDL

-reverses cholesterol transport

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27
Q

What are the two apolipoproteins that function on HDL?

A

ApoA-I

ApoE

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28
Q

What receptor is ApoE the ligand for?

A

LDL remnant receptor

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29
Q

Where is ApoE produced?

A

Liver AND Other tissues

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30
Q

What lipoproteins is the apoprotein ApoCII found on?

A

Chylomicrons

VLDL

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31
Q

What is the function of ApoCII?

A

Binds to lipoprotein lipase

-Enhances triglyceride hydrolysis

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32
Q

What is the function of LPL (Lipoprotein Lipase)?

A

-Found in capillaries of fat, cardiac, and skeletal muscle

-Breaks down chylomicrons (and triglycerides inside) into FFA

-FFA are taken up by peripheral tissues and adipose tissue (eventually go back to liver)

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33
Q

What is the function of HL (Hepatic Lipase)?

A

-Produced in liver

-Key in converting IDL to LDL

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34
Q

What is the major source of creation of cholesterol?

A

De novo synthesis in liver

*most critical to body burden

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35
Q

What ratio of TC to HDL is associated with increased risk of CVD?

A

> 4.5

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36
Q

What ratio of TC to HDL is desirable?

A

< or = 3.5

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37
Q

What ratio of TC to HDL is optimal?

A

< 3

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38
Q

What diseases are caused by hyperlipoproteinemia?

A

-Atherosclerosis (buildup of cholesterol in vascular smooth muscle)

-Premature coronary artery disease

-Neurologic disease (stroke)

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39
Q

What diseases are caused by hypertriglyceridemia?

A

-Pancreatitis

-Xanthomas

-Risk of CHD (fatty deposits in skin)

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40
Q

What cells make up an atherosclerotic plaque?

A

FOAM cells

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41
Q

What cells are LDL receptors present on?

A

Endothelial cells

-contributes to atherosclerotic plaque formation

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42
Q

What is the role of macrophages in atherosclerosis?

A

LDL deposits cholesterol into macrophages. These then become FOAM cells which make up the atherosclerotic plaque

-HDL tries to remove LDL from macrophages to prevent them from becoming FOAM cells

-Cholesterol can be hydrolyzed back to free cholesterol and effluxed from the macrophage

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43
Q

What is the role of ACAT1 and CEH?

A

-Make up the necrotic core of an atherosclerotic plaque

*ACAT1 changes a free cholesterol to cholesterol esterases

*CEH changes cholesterol esterases to free cholesterol which can then be removed from the macrophage

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44
Q

Why do we want to decrease VLDL?

A

It is secreted by the liver as a source of triglycerides

-Decreasing VLDL decreases the amount of triglycerides in the body

45
Q

A 10% decrease in cholesterol levels is associated with what percent decrease in the incidence of coronary heart disease?

A

10-30% decrease

46
Q

What 3 drugs are used for high triglycerides?

A

-Fibrates
-Niacin
-Omega 3 fatty acids

47
Q

What is the mechanism of action of bile acid-binding resins?

A

-Inhibit reabsorption of bile acids from the intestine through binding them to form insoluble complexes that get excreted in the feces
(this forces the liver to produce more bile acids and use up more cholesterol)

-Upregulate LDL receptors in the liver
(causes liver to take up more LDL which lowers free cholesterol levels)

48
Q

By how much are bile acid-binding resins able to increase bile acid secretion by the liver?

A

10% increase

49
Q

What are the two bile acid-binding resins?

A

-Cholestyramine

-Colestipol

50
Q

What is the chemistry/structure of bile acid-binding resins?

A

-Large molecular weight polymers

-Exchange chloride ions for bile acids

51
Q

What affect do bile acids have on LDL, HDL, and TG?

A

LDL: decrease by 20%
HDL: increase by 5%
TG: increase

52
Q

When are bile acid-binding resins taken?

A

Before meals

53
Q

What are the side effects of bile acid-binding resins?

A

Constipation

Bloating

54
Q

What is the mechanism of action of ezetimibe (zetia)?

A

-Inhibits cholesterol absorption in the intestines from the diet
-Inhibits reabsorption of cholesterol excreted in bile

55
Q

What transporter is inhibited by ezetimibe?

A

NPC1L1
(Neimann-Pick C1-Like 1

(plays a role in cholesterol reabsorption)

56
Q

What is the primary clinical effect of ezetimibe?

A

Reduction of LDL levels

57
Q

What are the adverse affects of ezetimibe?

A

-Liver/muscle damage

(rhabdomyolysis)

*low incidence, generally well tolerated

58
Q

What 2 statins are prodrugs?

A

Lovastatin

Simvastatin

*identified by presence of a lactam ring

59
Q

What 2 statins are not metabolized by CYP?

A

Pravastatin

Pitavastatin

60
Q

What is the mechanism of action of statins?

A

HMG-CoA reductase inhibitors

(this is the rate-limiting enzyme in cholesterol biosynthesis)

-Upregulate LDL receptors

61
Q

How does the HMG-CoA reductase work?

A

Acetyl CoA changes to HMG-CoA

HMG-CoA is reduced by the reductase to Mevalonic Acid

Mevalonic acid is synthesized into cholesterol

62
Q

When are statins indicated?

A

Hypercholesterolemia
(Elevated LDL
OR
Elevated LDL + TGs)

*After MI

63
Q

What statins are metabolized by CYP 3A4?

A

-Lovastatin
-Simvastatin
-Atorvastatin

64
Q

What statins are metabolized by CYP 2C9?

A

-Fluvastatin
-Rosuvastatin

65
Q

What statin is metabolized by sulfation?

A

-Pravastatin

66
Q

What statin is excreted unchanged in the bile?

A

Pitavastatin

*undergoes enterohepatic recirculation

67
Q

What are the adverse effects associated with statins?

A

-Rhabdomyolysis
(with renal dysfunction secondary to myoglobinuria)

-Hepatotoxicity

-Increased incidence of Type 2 Diabetes

68
Q

What drugs increase the risk for rhabdomyolysis when administered with statins?

A

-CYP inhibitors

-Gemfibrozil

69
Q

Who is more likely to experience hepatotoxicity when taking statins?

A

-Individuals with underlying liver disease

-Alcoholics

70
Q

What is the mechanism of action of bempedoic acid (Nexletol)

A

ATP-Citrate Lyase Inhibitor (ACL)

(an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway)

71
Q

When should bempedoic acid (Nexletol) be used?

A

-As an adjunct to statins

(For Heterozygous Familial Hypercholesterolemia (HeFH) or Atherosclerotic Cardiovascular Disease (ASCVD))

72
Q

How is bempedoic acid (Nexletol) metabolized?

A

Glucuronidation

-excreted by the kidneys

73
Q

What receptor does bempedoic acid inhibit?

A

OAT2

(in renal tubules)

74
Q

What are the side effects of bempedoic acid?

A

Hyperuricemia

Gout

75
Q

How do PCSK9 inhibitors work?

A

PCSK9 (proprotein convertase subtilisin kexin type 9) is a serine protease that promotes the degradation of LDL receptors in the liver

-Inhibiting this indirectly increases LDL receptors

-This leads to decreased free LDL

76
Q

What are the PCSK9 inhibitors?

A

-Alirocumab (Praluent)
-Evolocumab (Repatha)
-Inclisiran (Leqvio)

77
Q

What is the structure of Alirocumab (Praluent) and Evolocumab (Repatha)?

A

Human IgG Antibodies

78
Q

What is the structure of Inclisiran (Leqvio)

A

siRNA

79
Q

How does Inclisiran (Leqvio) work?

A

Hybridizes PCSK9 mRNA and directs degradation of PCSK9 in hepatocytes

80
Q

What are the indications for Alirocumab (Praluent) and Evolocumab (Repatha)?

A

*Used as adjunct to statins in:

ASCVD

HeFH + HoFH

81
Q

What are the indications for Inclisiran (Leqvio)?

A

*Used as adjunct to statins in:

ASCVD

HeFH

82
Q

What are the side effects associated with PCSK9 inhibitors?

A

-Injection site reactions

-Arthralgia (joint pain)

83
Q

What is the mechanism of action of Juxtapid (Lomitapide)?

A

-Inhibitor of MTTP

-Inhibits assembly of Apo B containing lipoproteins in liver AND intestines

83
Q

What is different in patients with homozygous familiar hypercholesterolemia?

A

LDL-receptor function is severely reduced

84
Q

What processes does Juxtapid (Lomitapide) interfere with?

A

Assembly of VLDL’s

Assembly of chylomicrons

85
Q

When is Juxtapid (Lomitapide) given?

A

As an adjunct in patients with homozygous familiar hypercholesterolemia

86
Q

What are the two inhibitors of Apo B lipoprotein synthesis?

A

Juxtapid (Lomitapide)

Mipomersen (Kynamro)

87
Q

What are the side effects associated with the Apo B lipoprotein synthesis inhibitors?

A

Liver damage!

Hepatic steatosis (fatty liver)

88
Q

What is the mechanism of action of Mipomersen (Kynamro)?

A

-Phosphorothioate anti-sense oligonucleotide inhibitor of Apo B100

-Hybridizes Apo B100 mRNA in the liver and promotes degradation

89
Q

What is the one angiopoietin-like Protein 3 inhibitor drug?

A

Evinacumab-dng (Evkeeza)

90
Q

What is Evinacumab-dgnb (Evkeeza) used for?

A

Homozygous Familial Hypercholestoralemia

91
Q

What is the mechanism of action of Evinacumab-dgnb (Evkeeza)

A

-Inhibits Angiopoietin-like Protein 3

-Increases lipoprotein lipase (LPL) and endothelial lipase (EL) by preventing ANGPTL3 mediated inhibition

-Lowers LDL

92
Q

Does the angiopoietin-like protein 3 inhibitor evinacumab-dgnb (Evkeeza) require LDL-receptors?

A

No

93
Q

what are the two fibric acid derivatives (fibrates) used in the US?

A

Gemfibrozil

Fenofibrate

94
Q

What is the mechanism of action of fibrates?

A

-Bind to PPAR-a and regulate gene transcription along with the retinoic acid receptor (RXR)

95
Q

What are the indications of fibrates?

A

-Hypertriglyceridemia (VLDL predominate)

-Second line for mixed hyperlipidemia

96
Q

What are the side effects of fibrates?

A

-Gallstones

-Skeletal muscle effects (rhabdomyolysis)

Use Caution With Statins
(increased rhabdomyolysis risk)

97
Q

What drug interactions exist with fibrates?

A

-Increase warfarin effects

-Use with statins increases rhabdomyolysis risk

98
Q

What is the mechanism of action of niacin?

A

*Decreases TG levels

-Vitamin at dietary level
-Increases lipase activity to increase clearance of VLDL

99
Q

What is the function of niacin in the adipose tissue?

A

-Inhibits TG lipolysis by hormone-sensitive lipase

-Decreases FA transport to liver

-Done by activating GPR109A

100
Q

What receptor is activated by niacin in the adipose tissue?

A

GPR109A

101
Q

What is the function of niacin in the liver?

A

-Inhibits fatty acid synthesis and esterification

-Reduces TG export via VLDL

-Reduces clearance of apoA-I but not cholesterol esters!

(increases HDL levels and reverse transport)

102
Q

What is the function of niacin on macrophages?

A

Increases expression of CD36 and ABCA1

-Decreases cholesterol ester content through HDL-mediated reverse transport

103
Q

What are the adverse effects associated with niacin?

A

-Vasodilation (flushing)

-Hepatotoxicity

104
Q

What are the 3 Omega-3-fatty acid ethyl ethers?

A

-Lovaza

-Omtryg

-Vascepa

105
Q

What is the mechanism of action of omega-3-fatty acids?

A

-Reduce triglyceride synthesis in liver
(act as poor substrates for enzymes responsible for TG synthesis)

-Inhibit esterification of other fatty acids

106
Q

What is an important note about Lovaza (omega-3-fatty acid)?

A

-Should initiate a lipid lowering diet before starting

107
Q

When are omega-3-fatty acids indicated?

A

Severe hypertriglyceridemia >500 mg/dl

108
Q

What are the adverse effects of omega-3-fatty acids?

A

Increase LDL levels

Therapeutics 2 Exam 5 (9 decks)

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