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Therapeutics II > Anti-Hyperlipidemics > Flashcards

Anti-Hyperlipidemics Flashcards

1
Q

What is cholesterol?

A

-Essential component of cell membranes
-Precursor to sterols and steroids

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2
Q

What are triglycerides?

A

-Storage form of fuel to support generation of high energy compounds
-Component of structural lipids

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3
Q

What do lipoproteins do?

A

Lipoproteins transport cholesterol and triglycerides in the blood

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4
Q

What are lipoproteins made of?

A

-Phospholipid, free cholesterol, and protein making up the surface
-Core made of triglyceride and cholesterol ester

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5
Q

What do apoproteins do?

A

Critical in regulating transport and metabolism

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6
Q

What does the lipoprotein lipase system do?

A

Release free fatty acids from lipoproteins

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7
Q

What are the major classes of lipoproteins?

A

-Chylomicrons
-VLDL
-IDL
-LDL
-HDL

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8
Q

What are chylomicrons?

A

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

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9
Q

What is VLDL?

A

Very low density lipoproteins are secreted by the liver into the blood as a source of triglycerides

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10
Q

What is IDL?

A

Intermediate density lipoproteins - VLDLs when they are depleted of triglyceride

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11
Q

What is LDL?

A

Low density lipoproteins are the main form of cholesterol in the body

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12
Q

What is HDL?

A

High density lipoproteins are secreted by the liver and acquire cholesterol from peripheral tissues and atheromas through reverse cholesterol transport

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13
Q

What are the important apolipoproteins?

A

-ApoA-I
-ApoB-100
-ApoB-48
-ApoE
-APoCII

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14
Q

What are the characteristics of ApoA-I

A

-Structural in HDL
-Ligand of ABCA1 receptor
-Mediates reverse cholesterol transport
-Produced in the liver and intestine

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15
Q

What are the characteristics of ApoB-100?

A

-Structural in VLDL, IDL, LDL
-LDL receptor ligand
-Produced in the liver

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16
Q

What are the characteristics of ApoB-48

A

-Structural in chylomicrons
-Produced in the intestine

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17
Q

What are the characteristics of ApoE?

A

-Ligand of LDL remnant receptor
-Reverse cholesterol transport with HDL
-Produced in the liver and other tissues

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18
Q

What are the characteristics of ApoCII?

A

-Found in chylomicrons and LDL
-Binds to lipoprotein lipase to enhance triglyceride hydrolysis
-Found typically in the capillaries where fatty acid transport happens

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19
Q

Where can lipoprotein lipase be found?

A

In capillaries of fat, cardiac and skeletal muscle

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20
Q

Where can hepatic lipase be found?

A

Produced in the liver and is key in converting IDL to LDL

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21
Q

Which molecule is key in making cholesterol?

A

Mevalonate

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22
Q

Which cholesterol synthesis is the major source of cholesterol

A

De novo synthesis

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23
Q

Which cholesterol synthesis is most critical to total body burden?

A

Liver synthesis

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24
Q

Which diseases are associated with hyperlipoproteinemia?

A

-Atherosclerosis
-Premature coronary artery disease
-Stroke

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25
Q

Which diseases are associated with hypertriglyceridemia?

A

-Pancreatitis
-Xanthomas
-Increased risk of CHD

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26
Q

What is oxidized LDL?

A

-Modified LDLs
-Stimulates T cells in the intima
-Gets into areas between the endothelium of the blood vessel

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27
Q

How does LDL get into the macrophage?

A

-LDL gets in through pinocytosis and the LDLR protein
-Oxidized LDL gets in through the SR-A and CD36 proteins

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28
Q

What does the lysosome do in the macrophage?

A

Breaks down LDL into free cholesterol

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29
Q

What are the two fats of free cholesterol in the macrophage?

A

-Esterified into cholesterol ester by ACAT1
-Transported out of the macrophage through the HDL mediated proteins ABCA1, SR-BI, or ABCG1

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30
Q

What are the goals of therapy for hyperlipidemia?

A

-Decrease reabsorption of excreted bile acids
-Increase number of LDL receptors in the liver
-Decrease secretion of VLDL from the liver
-Decrease synthesis of cholesterol
-Increase hydrolysis of lipoprotein triglycerides
-Ultimately the goal is to reduce atherosclerosis

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31
Q

How much of a reduction in the incidence of coronary heart disease is associated with a 10% reduction in cholesterol levels?

A

~10-30% reduction

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32
Q

Which drug classes are used for high cholesterol?

A

-Bile acid binding resins
-Inhibitors of cholesterol absorption
-Inhibitors of cholesterol synthesis
-PCSK9 inhibitors
-MTTP inhibitors

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33
Q

Which drug classes are used for high triglycerides?

A

-Fibrates
-Niacin
-Omega 3 fatty acids

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34
Q

What are the bile acid-binding resins?

A

-Cholestyramine (Queastran)
-Colestipol (Colestid)

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35
Q

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

A

-Inhibit reabsorption of bile acids from the intestine by binding bile acids to form insoluble complex excreted in the feces
-Up-regulates LDL receptors in the liver
-Large molecular weight polymers exchange chloride ions for bile acids

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36
Q

Therapeutic use of bile acid binding resins

A

-Treatment of primary hypercholesterolemia produces ~20% reduction in LDL cholesterol in 2-4 weeks
-May cause ~5% increase in HDL
-May increase TG

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37
Q

Side effects of bile acid binding resins

A

-Constipation and bloating
-High fiber diet and water helps

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38
Q

Drugs that interact with bile acid binding resins

A

-Acetaminophen
-Thiazides
-Warfarin
-Digoxin
-Fibrates
-Ezetimibe
-Oral contraceptive
-Corticosteroids
-Thiazolidinediones

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39
Q

What is the cholesterol absorption inhibitor?

A

Ezetimibe

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40
Q

What is the mechanism of action of ezetimibe?

A

Inhibits intestinal absorption of cholesterol from dietary sources and reabsorption of cholesterol excreted in bile (inhibits NPC1L1)

41
Q

What is the indication for ezetimibe?

A

The primary clinical effect is to reduce LDL levels (~17%)
-Usually used in combination with statins (may enhance statin action up to 20%)

42
Q

What are the adverse effects associated with ezetimibe?

A

-Low incidence of liver/skeletal muscle damage
-Generally well tolerated compared to placebo

43
Q

What is the common pharmacophore of statins?

A

Mevalonic acid

44
Q

Which statins are prodrugs?

A

Lovastatin and simvastatin

45
Q

Which statins are not CYP substrates?

A

Pravastatin and pitavastatin

46
Q

What is the mechanism of action for statins?

A

-Competitively inhibit HMG-CoA reductase which is the rate-limiting enzyme in cholesterol biosynthesis
-Up-regulates LDL receptors enabling more LDL to be delivered to the liver, thus reducing plasma cholesterol

47
Q

What are all of the statin drugs?

A

-Fluvastatin
-Rosuvastatin
-Atorvastatin
-Lovastatin
-Simvastatin
-Pravastatin
-Pitavastatin

48
Q

Indications for statin drugs

A

-Hypercholesterolemia: elevated LDL; elevated LDL with slightly elevated TGs
-Standard practice to initiate therapy immediately after a myocardial infarction, irrespective of lipid levels

49
Q

Expected results of statins

A

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

50
Q

Which statins are metabolized by CYP 3A4?

A

-Lovastatin
-Simvastatin
-Atorvastatin

51
Q

Which statins are metabolized by CYP 2C9?

A

-Fluvastatin
-Rosuvastatin

52
Q

Adverse effects associated with statins

A

-Rhabdomyolysis (increased incidence when co-administered with cyp inhibitors; may occur with fibrates such as gemfibrozil)
-Hepatotoxicity
-Increased incidence of type 2 diabetes

53
Q

What is the ATP-Citrate Lyase inhibitor?

A

Bempedoic acid

54
Q

How is bempedoic acid taken?

A

-Orally
-Once daily
-Adjunct to statins

55
Q

What is ATP-Citrate Lyase?

A

ACL is an enzyme upstream of HMG-CoA in the cholesterol synthetic pathway

56
Q

What is bempedoic acid indicated in?

A

Added to statin therapy in patients with heterozygous familial hypercholesterolemia or established cardiovascular disease

57
Q

How is bempedoic acid metabolized?

A

By glucuronidation and excreted via the kidneys

58
Q

What are some possible side effects that can occur with bempedoic acid?

A

Hyperuricemia and gout because of the inhibition of OAT2 in renal tubules

59
Q

What are the PCSK9 inhibitors?

A

-Alirocumab
-Evolocumab
-Inclisiran

60
Q

What is PCSK9?

A

-Proprotein convertase subtilisin kexin type 9 (a serine protease)
-Promotes degradation of LDL receptors in the liver

61
Q

How are PCSK9 inhibitors taken?

A

Injected subq every two weeks or once a month for evolocumab

62
Q

What are PCSK9 inhibitors indicated in?

A

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

63
Q

What is the newer PCSK9?

A

Inclisiran

64
Q

How does inclisiran work?

A

It is an siRNA that hybridizes PCSK9 mRNA and directs degradation in hepatocytes to lower LDL cholesterol

65
Q

When is inclisiran used?

A

-Used as an adjunct to statins in HeFH and ASCVD

66
Q

Side effects of inclisiran

A

-Injection site reactions
-Arthralgia

67
Q

What is juxtapid?

A

Small molecule microsomal TG transfer protein inhibitor

68
Q

What does juxtapid do?

A

Inhibits assembly of Apo B containing lipoproteins in the liver (VLDL production) and intestine (chylomicron production)

69
Q

How is juxtapid given?

A

-Orally
-Daily, with increases in dose every two weeks

70
Q

What is juxtapid indicated in?

A

Adjunct to other treatments for patients with homozygous familial hypercholesterolemia - LDLR mutation

71
Q

What is a warning associated with juxtapid?

A

High risk of liver damage - restricted prescription program

72
Q

What is mipomersen?

A

Phosphorothioate anti-sense oligonucleotide inhibitor of Apo B100 (liver)

73
Q

What does mipomersen do?

A

Hydrolizes Apo B100 mRNA in the liver and promotes degradation

74
Q

How is mipomersen taken?

A

Injected SQ once/week

75
Q

What is mipomersen indicated in?

A

indicated as adjunct to other treatments for patients with homozygous familial hypercholesterolemia

76
Q

What is a risk associated with mipomersen?

A

High risk of liver damage - restricted prescription program hepatic steatosis

77
Q

What does evinacumab-dgnb do?

A

Increases lipoprotein lipase and endothelial lipase activity by preventing ANGPTL3 mediated inhibition. Lowers LDL-cholesterol

78
Q

How is evinacumab-dgnb given?

A

IV infusion once per month

79
Q

What does evinacumab-dgnb indicated for?

A

Homozygous familial hypercholesterolemia

80
Q

What are the fibrates?

A

Gemfibrozil and fenofibrate

81
Q

What do fibrates target?

A

Peroxisome proliferator-activated receptor-alpha activatrors

82
Q

What are fibrates derived from?

A

Branched carboxylic acid know as fibric acid

83
Q

What is the difference between gemfibrozil and fenofibrate?

A

Fenofibrate must undergo bioactivation to fenofibric acid

84
Q

Expected results of fibric acid derivatives

A

-Reduce serum LDL by 6-20%
-Reduce serum TGs by 35-53%
-Elevate HDL 15-30%

85
Q

Therapeutic indications for fibric acid derivatives

A

-Hypertriglyceridemia in which VLDL predominate
-Second line drug for mixed hyperlipidemia

86
Q

Side effects associated with fibric acid derivatives

A

-Gallstones
-Rhabdomyolysis (Use with caution with statins)

87
Q

What drug can interact with fibric acid derivatives?

A

Warfarin

88
Q

What is the mechanism of action of niacin?

A

-Reduce serum triglycerides
-Increases lipase activity to increase clearance of VLDL
-Decreases hepatic VLDL production
-May significantly reduce serum LDL and TG
-Usually increases HDL levels

89
Q

What tissues does niacin target?

A

-Adipose tissue
-Liver
-Macrophages

90
Q

How does niacin effect adipose tissue?

A

Inhibits TG lipolysis by hormone-sensitive lipase decreasing FS transport to liver via activation of GPR109A

91
Q

How does niacin effect liver tissue?

A

-Inhibits fatty acid synthesis and esterification reducing TG export via VLDL
-Reduces clearance of apoA-I but not CEs increasing HDL levels and reverse transport

92
Q

How does niacin effect macrophages?

A

Increases expression of CD36 and ABCA1 decreasing CE content via HDL-mediated reverse transport

93
Q

Indications for niacin

A

-Effective for mixed hyperlipidemias
-Hypertriglyceridemia with risk of pancreatitis (decreases TG 25-30%)
-Effective drug for raising HDL levels (15-35%)
-Used in combination with resin drugs to treat severe cases of hyperlipidemia; also combined with statins

94
Q

Adverse effects associated with niacin

A

-Marked vasodilation (cutaneous flushing), itching, tingling of upper body and headache may occur with initial dosing - prostaglandins mediate these
-Hepatotoxicity - sustained release preparations

95
Q

What are the omega-3-fatty acid ethyl esters?

A

-Lovaza, Omtryg (EPA + DHA)
-Vascepa (EPA only)

96
Q

Mechanism of action of omega-3-fatty acid ethyl esters

A

-Reduce synthesis of triglycerides in the liver: omega-3 fatty acids are poor substrates for enzymes responsible for TG synthesis
-Inhibits esterification of other fatty acids

97
Q

Indications of omega-3-fatty acids

A

-Lipid lowering diet is initiated before Lovaza is started
-Severe hypertriglyceridemia >500 mg/dl

98
Q

Adverse effects of omega-3-fatty acids

A

-Can increase LDL-C levels (only the combo products)
-Combined with statins to lower LDL-C levels

Therapeutics II (33 decks)

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