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Pharmacology > EXAM #2: ANTIHYPERLIPIDEMICS > Flashcards

EXAM #2: ANTIHYPERLIPIDEMICS Flashcards

1
Q

Draw the overview of lipid metabolism.

A

N/A

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2
Q

Describe the structure of a lipoprotein.

A
  • Inner core of cholesterol and cholesterol esters

- Outer phospholipid monolayer interposed with unesterified cholesterol and apolipoproteins

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3
Q

How does the density and structure of the lipoproteins compare to one another?

A 
Chylomicrons= least dense
HDL= most dense

Generally, the more dense means less TGs and more cholesterol

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4
Q

What apolipoproteins are associated with Chylomicrons?

A

B-48, C, E, & A

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5
Q

What apolipoproteins are associated with VLDL?

A

B-100, C, & E

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6
Q

What apolipoproteins are associated with LDL?

A

B-100

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7
Q

What apolipoproteins are associated with HDL?

A

A-I, A-II, C, E, & D

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8
Q

What are the functions of apolipoproteins?

A

1) Cofactors for enzymes in lipid metabolism
2) Ligands for receptors
3) Structural stability of lipoproteins

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9
Q

What is the role of NPC1L1? What drug inhibits this transporter?

A

Transporter responsible for the uptake of dietary cholesterol into the enterocytes

Inhibited by Ezetimibe

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10
Q

Outline the enterohepatic circulation of bile salts.

A
  • Bile salts are SYNTHESIZED in the liver from cholesterol
  • STORED in the gallbladder and SECRETED into the duodenum
  • Most are reabsorbed but some are excreted in the feces

Bile acid resins will increases the fecal excretion of cholesterol*

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11
Q

What is the function of ApoB-48?

A

Structural integrity of lipoproteins

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12
Q

What is the function of ApoC-II? What happens when ApoC-II is nonfunctioning?

A

For dietary lipids to be removed from the circulation, lipoprotein lipase (LPL) must be activated; this requires ApoC-II

Malfunction results in v. high TG levels in the blood*

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13
Q

How is excess cholesterol eliminated? What organ facilitates this process?

A

Liver

  • Cholesterol is converted into bile acids and bile salts
  • Secreted into the intestines
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14
Q

Describe the reverse transport of cholesterol.

A

1) HDL contains ApoA-1 and the transporter, ABAC1, that allows HDL to accept cholesterol from peripheral macrophages
2) LCAT converts cholesterol to cholesterol esters in HDL
3) HDL is transported to the liver and binds to the hepatocyte via interactions with ApoA-1 on HDL and the SR-B1 receptor on the hepatocyte

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15
Q

What are the characteristics of dylipidemia?

A
  • Elevated total and LDL cholesterol

- Low HDL

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16
Q

What are the goals of the clinical management of dyslipidemia?

A

1) Prevent acute pancreatitis

2) Prevent CAD

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17
Q

What are the primary/ monogenic types of hyperlipidemia?

A

Hyperlipidemia caused by single gene mutation

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18
Q

What are the polygenic-environmental types of hyperlipidemia?

A

Hyperlipidemia caused by a combination of genetics and environment

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19
Q

Outline the stages of atherosclerosis.

A
  • Normal
  • Fatty streak
  • Fibrous plaque
  • Occlusive atherolsclerotic plaque
  • Plaque rupture/ thrombosis
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20
Q

What are the major risk factors for atherosclerosis?

A

1) Age/male gender
2) Smoking
3) HTN
4) Dyslipidemia
5) DM
6) Family history

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21
Q

What is the cause of primary chylomicronemia? What are the manifestations of the disease?

A

Cause: Defect in lipoprotein lipase (LPL)

Effect: increased chylomicrons and VLDL

**Recall that LPL breaksdown TGs in chylomicrons and VLDL into FFAs and glycerol**

22
Q

What is the cause of familial hypertriglyceridemia? What are the manifestations of the disease?

A

Cause: polygenic impairment of VLDL and/or chylomicrons removal

Effect: Elevated VLDL and chylomicrons

23
Q

What is the cause of familial combined hyperlipoproteinemia? What are the manifestations of the disease?

A

Cause: Polygenic increase in VLDL production

Effect: Increased VLDL, LDL or both

24
Q

What is the cause of dysbetalipoproteinemia? What are the manifestations of the disease?

A

Cause: absence of ApoE

Effect: decreased clearance of VLDL, IDL, and chylomicrons remnants, resulting in increased IDL and chylomicrons

25
Q

What causes familial hypercholesterolemia? What is the manifestation of the disease?

A

Cause: LDLR impairment

EffecT: Increased LDL

26
Q

What is the cause of familial ligand defective ApoB? What are the manifestations of the disease?

A

Cause: ApoB-100 mutations such that receptor-mediated endocytosis of LDL is impaired (liver and periphery)

Effect: Increased LDL

27
Q

List the fibrates.

A

Gemfibrozil

Fenofibrate

28
Q

What is the mechanism of action of the fibrates?

A

PPAR activator i.e. activation of a transcription factor that:

  • Increases fatty acid oxygenation
  • Decreases Apo C-III synthesis (LPL inhibitor)
  • Increases LPL expression
  • Increased apoA-I, and apoA-II

****Net effect is decreased TG and INCREASED HDL

29
Q

What diseases would the fibrates be used to treat?

A

1) Hypertriglyceridemias
- Primary chylomicroenemia
- Familial hypertriglyceridemia
- Familial combined hyperlipoproteinemia
- Familial dysbetalipoproteinemia
- Secondary hypertriglyceridemia

2) Mixed hyperlipidemia

30
Q

What are the adverse effects of the fibrates?

A

Picmonic: Liver toxicity and gallstones +

  • Rash
  • GI symptoms
  • Myopathy
31
Q

List the bile acid-binding resins.

A

Cholestyramine
Colesevelam
Colestipol

32
Q

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

A

1) Bind bile acids and bile salts in intestine
2) Increased excretion of bile acids requires the liver to use cholesterol to synthesize more bile acids/ salts
- Causes and increase in LDL receptor density on the liver

33
Q

What are the bile acid-binding resins used to treat?

A

Familial hypercholesterolemia

Note that these are commonly used now in conjunction with statins

34
Q

What is the effect of bile acid-binding resins on LDL and TG?

A
  • Decreased plasma LDL
  • INCREASED plasma TG

**Thus, these drugs should NOT be given to patients with HYPERTRIGLYCERIDEMIA

35
Q

What class of drugs is used to treat hyperlipidemia in women and children? Why?

A

Bile acid binding resins

B/c they are NOT systemically absorbed**

36
Q

What is the mechanism of action of Niacin?

A
  • Binds to a GPCR, on adipocytes
  • Binding inhibits adipocyte hormone-sensitive lipase
  • This lipase would DECREASE plasma FFA
  • LESS plasma FFA = decreased synthesis of TGs by the liver, and less VLDL

Also, Niacin INCREASES HDL production*

37
Q

What is Niacin used to treat?

A

All hypercholesterol and hypertriglyceridemias

38
Q

What side effects are associated with Niacin?

A
  • Cutaneous flushing and itching (prostacyclin in the skin)
  • Hyperuricimia (Gout)
  • Hepatotoxicity
  • Myopathy–risk increased with statin use
39
Q

What causes the flushing seen in Niacin therapy?

A

Nicain induced secretion of prostacyclins from the skin

40
Q

List the inhibitors of cholesterol absorption.

A

Ezetimibe

41
Q

What is the mechanism of action of Ezetimibe?

A

NPC-1L1 antagonist that blocks uptake of dietary cholesterol, which:

  • Reduces cholesterol incorporation into chylomicrons
  • Less chylomicrons to the liver decreases plasma LDL levels

Note that this drug is commonly used in conjunction with statin therapy*

42
Q

What diseases is Ezetimibe used to treat?

A

All hypercholesterolemia

43
Q

List the statins.

A 
Atorvastatin 
Fluvastatin 
Lovastatin
Pitavastatin
Rosuvastatin 
Simvastatin
44
Q

What is the mechanism of action of the statins?

A
  • HMG-COA reductase inhibitors i.e. inhibit cholesterol synthesis
  • Increased expression of LDL receptor (hepatic and extra-hepatic tissues)
  • Increased LDL endocytosis and LOWERED LDL plasma levels
45
Q

What are most potent statins?

A

Atorvastatin and rosuvastatin

46
Q

What is the least potent statins?

A

Fluvastatin

47
Q

What are the “pleotropic” effects of stains?

A

1) Decreased coagulation
2) Decreased platelet activation

Important to note that there are numerous effects of statins that are cardioprotective in ADDITION to their effect on plasma cholesterol

48
Q

What are the clinical indications for statin therapy?

A

All hypercholesterolemias but clinically prescribed to treat individuals with:

  • Elevated LDL and a 10-year CAD risk
  • Clinically evident CAD
49
Q

What are the adverse effects of statins?

A

1) Myopathy
2) Myositis
3) Rhabdomyolysis
4) Liver toxicity

Note that elevated liver enzymes ALONE does not necessitate the cessation of statin therapy; elevated + BILIRUBIN is the indication that therapy should be stopped

50
Q

When is statin therapy contraindicated?

A

Pregnancy

Pharmacology (64 decks)

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