Chapter 24: Lipid-Lowering Drugs

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1

What protein transports fatty acids in the blood?

albumin

2

How are triglycerides transported in the blood?

lipoproteins

3

What is the term for elevated lipoprotein levels?

hyperlipidemia

4

What is the term for elevated plasma triglycerides without elevated cholesterol?

hyperlipemia

5

What is caused by development of fatty streaks and plaques in large and medium-sized arteries?

atherosclerosis

6

The clinical manifestations of atherosclerosis depends on the degree to which the lesions have progressed in a particular part of the vasculature. What are three effects of atheromatous lesions on the circulation to a prescribed area?

  1. obstruction by plaques or thrombi
  2. loss of vascular reactivity and control
  3. weakening or rupture of vessels
7

Foam cells are a primary characteristic of atheromatous plaques. How do foam cells from?

As macrophages engulf lipoproteins, metabolize cholesterol to cholesteryl esters, and accumulate cholesteryl ester-laden vesicles, they eventually die and contribute to plaque formation.

8

Classification of plasma lipoproteins is based on the density of the complexes. What are the seven major classes of lipoproteins?

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  1. chylomicrons
  2. chylomicron remnants
  3. very low-density lipoproteins (VLDL)
  4. intermediate-density lipoproteins (IDL)
  5. low-density lipoproteins (LDL)
  6. high-density lipoproteins (HDL)
  7. lipoprotein(a)
9

Which are the the largest lipoproteins particles, possessing the greatest proportion of lipid?

chylomicrons

10

Two separate lipoprotein-producing systems or metabolic pathways are responsible for the transport of lipids. What are they?

exogenous pathway and endogenous pathway

11

Two separate lipoprotein-producing systems or metabolic pathways are responsible for the transport of lipids. Which pathway involves production of chylomicrons in the intestinal mucosa from dietary fatty acids and cholesterol?

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exogenous pathway

12

Two separate lipoprotein-producing systems or metabolic pathways are responsible for the transport of lipids. Which pathway involves production of VLDL in the liver from fatty acids and cholesterol?

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endogenous pathway

13

Specific proteins associated with lipoprotein particles play a crucial role in lipoprotein metabolism. What are these proteins called?

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apoproteins

14

Which apoprotein is the major protein component of chylomicrons, forming an the amphipathic coating of the particle?

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apoprotein B48

15

The exogenous pathway of lipid transport begins with formation of chylomicrons in the intestine. What enzyme degrades chylomicrons in the capillary endothelium of muscle and adipose tissue?

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lipoprotein lipase

16

Lipoprotein lipase is attached to the luminal surface of endothelial cells of capillaries located in the adipose tissue, skeletal muscles, and heart. What serves as a stimulus for endothelial lipase activity?

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apoprotein CII

17

In the peripheral tissues, chylomicron triglycerides are degraded to by the enzyme lipoprotein lipase. What happens to the chylomicron remnants that are released back into circulation?

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They are actively taken up by LRP (LDL receptor-related protein, a member of the LDL receptor family) on the surface of hepatocytes.

18

The endogenous pathway of lipid transport begins with hepatic synthesis of VLDL particles. What enzyme assembles VLDL in the endoplasmic reticulum from cholesterol esters, triglycerides, and apolipoprotein B100?

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microsomal triglyceride transfer protein (MTTP)

19

VLDL synthesized in the liver is secreted into circulation, where it is subject to attack in peripheral tissues by lipoprotein lipase. What is formed from degradation of VLDL by lipoprotein lipase?

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IDL

20

IDL can either undergo (1) lysosomal degradation by the liver or (2) further removal of triglyceride by hepatic lipase. What is formed from degradation of IDL by hepatic lipase?

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LDL

21

The synthesis of cholesterol, regulated by the initial enzyme of the pathway is an energetically expensive process, thus maintenance of total body cholesterol is a priority. What are the two mechanisms by which cholesterol is conserved?

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enterohepatic cycling and reverse cholesterol transport

22

Cholesterol is conserved through enterohepatic cycling and reverse cholesterol transport. What four steps are involved in enterohepatic cycling?

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  1. synthesis of cholesterol and conversion to bile acids by the liver
  2. secretion of bile acids into the small intestine
  3. absorption of bile acids from the terminal ileum
  4. transfer through the hepatic portal system and reuptake by the liver
23

Cholesterol is conserved through enterohepatic cycling and reverse cholesterol transport. What happens in reverse cholesterol transport?

HDL synthesized by the liver and intestine takes up cholesterol from peripheral cells and transports it back to the liver.

24

Which is the lipoprotein group most directly associated with coronary heart disease?

LDL

25

Which is the lipoprotein group correlated with decreased risk of coronary heart disease?

HDL

26

What drug class do the following belong to?

  • clofibrate
  • gemfibrozil
  • fenofibrate
  • bezafibrate
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fibric acid derivatives

27

What is the mechanism of action of fibric acid derivatives?

They act as ligands for the DNA transcription regulator PPARα, modifying rates of synthesis of specific enzymes.

28

What are the effects of fibric acid derivatives on lipoprotein concentrations?

  1. ↓ VLDL
  2. ↓ IDL
  3. ↑ HDL
29

What are the adverse effects of fibric acid derivatives?

  1. abdominal pain
  2. diarrhea
  3. nausea
  4. vomiting
30

Which B vitamin has the broadest spectrum of activity of the lipid-lowering agents?

nicotinic acid

31

What is the mechanism of action of nicotinic acid?

It inhibits of VLDL synthesis through inhibition of adipose tissue lipolysis and subsequent delivery of fatty acids to the liver.

32

What are the effects of nicotinic acid on lipoprotein concentrations?

  1. ↓ chylomicrons
  2. ↓ VLDL
  3. ↓ IDL
  4. ↓ LDL
  5. ↑ HDL
33

What are the adverse effects of nicotinic acid?

  1. cutaneous flushing
  2. pruritus
  3. gastrointestinal distress
34

What class of drug do the following belong to?

  • cholestyramine
  • colestipol
  • colesevelam

bile acid sequestrants

35

What is the mechanism of action of bile acid sequestrants?

They bind bile acids in the intestinal lumen, promoting their excretion in the feces, thereby increasing hepatic cholesterol conversion to bile acids by negative feedback.

36

What are the effects of bile acid sequestrants on lipoprotein concentrations?

  1. ↑ VLDL (transient)
  2. ↓ LDL
37

What are the adverse effects of bile acid sequestrants?

  1. nausea
  2. vomiting
  3. abdominal distention
  4. constipation
38

How do bile acid sequestrants interact with other drugs?

They bind to anionic drugs (e.g. warfarin, thyroxine, digitalis, propranolol, thiazides) in the intestine, decreasing absorption.

39

What class of drug do the following belong to?

  • lovastatin
  • pravastatin
  • simvastatin
  • fluvastatin
  • atorvastatin
  • rosuvastatin
  • pitavastatin
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statins

40

What is the mechanism of action of statins?

They are potent competitive antagonists of HMG-CoA, the rate-controlling enzyme in the pathway of cholesterol synthesis.

41

The statin-induced depletion of hepatic cholesterol has three effects. What are they?

  1. feedback inhibition of HMG-CoA reductase transcription is released, but the statin inhibits the new enzyme
  2. synthesis of hepatic LDL receptors is stimulated, resulting in increased hepatic uptake of LDL
  3. increase in the synthesis of PCSK9, which limits the effectiveness of statins at higher dosages
42

HMG-CoA reductase inhibitors are the most commonly prescribed lipid-lowering drugs. What are the effects of HMG-CoA reductase inhibitors on lipoprotein concentrations?

  1. ↓ IDL
  2. ↓ LDL
  3. ↑ HDL
43

What are the adverse effects of HMG-CoA reductase inhibitors?

  1. myalgia, myopathy
  2. blurred vision
  3. constipation, diarrhea, gas
  4. dizziness, headache, nausea
  5. skin rash
  6. impotence
  7. insomnia
44

What pregnancy category are statins?

category X

45

At high doses, statins become self-limiting because they stimulate the hepatic synthesis PCSK9. How does this limit the efficacy of statins?

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In the absence of PCSK9, the LDL receptor/LDL particle complex is internalized, the particle is metabolized, and the receptor is recycled to the plasma membrane to bind more LDL particles.

When is bound to PCSK9 binds the LDL receptor when the complex, is internalized, both the LDL particle and the LDL receptor are metabolized, causing LDL receptor downregulation.

46

What disease is associated with coronary heart disease and may have heart attacks at a very early age (before puberty)?

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homozygous familial hyperlipidemia

47

Since patients with homozygous familial hyperlipidemia have mutations in both alleles of the LDL receptor gene, statins have little or no efficacy. What two drugs are approved for use in these patients?

mipomersen and lomitapide

48

What is the mechanism of action of mipomersen?

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It is an antisense oligonucleotide drug that targets mRNA encoding apolipoprotein B, reducing its synthesis and synthesis of VLDL.

49

What is the mechanism of action of lomitapide?

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It inhibits MTTP, reducing assembly of VLDL in the liver and chylomicrons in the intestinal mucosa.

50

What do both mipomersen and lomitapide carry a boxed warning for?

hepatotoxicity

51

What pregnancy category are mipomersen and lomitapide?

category X

52

Another class of lipid-lowering drugs to be developed and approved for use are cholesterol absorption inhibitors. What is the mechanism of action of ezetimibe?

It is a inhibits the transporter Niemann-Pick C-1-like 1 protein (NPC1L1), reducing absorption of cholesterol.

53

Evidence exists to support a role for polyunsaturated fish oils in decreasing plasma lipid concentrations. What is the mechanism of action of fish oils in reducing levels of triglycerides?

The omega-3 fatty acids eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) can inhibit the synthesis of VLDL.

54

What are three benefits of combined lipid-lowering drug therapy?

  1. to achieve more profound reduction of lipid levels
  2. to overcoming unwanted elevations in certain lipids
  3. to allow smaller doses, decreasing potential side effects