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Pharmacology B > Lecture 2 - Lipid Disorders > Flashcards

Lecture 2 - Lipid Disorders Flashcards

1
Q

Buildup of LDL cholesterol favours ________

A

atherosclerosis

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2
Q

Define atherosclerosis

A

abnormal deposition of cholesterol arteries

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3
Q

What are triglycerides?

A

primarily chylomicrons, VLDLs as well

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4
Q

What is cholesterol primarily derived from?

A

LDL’s

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5
Q

As you lower LDL levels, you lower chance of ??

A

coronary events

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6
Q

How do you decrease cholesterol by decreasing GI uptake?

A
  • decrease dietary intake
  • decrease reabsorption of bile acids
  • decrease absorption of cholesterol
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7
Q

How do you decrease cholesterol by decreasing LDL levels?

A
  • decrease VLDL

- increase LDL receptors

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8
Q

What is another way to decrease cholesterol?

A

-decrease endogenous cholesterol synthesis

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9
Q

List the 3 potential sites to decrease cholesterol

A

1) decrease GI uptake
2) decrease LDL levels
3) decrease endogenous cholesterol synthesis

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10
Q

List non-pharms to help decrease cholesterol

A
  • increased dietary fibre

- increase omega-3 fatty acids

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11
Q

What are statins?

A

HMG-CoA Reductase Inhibitors

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12
Q

List some HMG-CoA Reductase Inhibitors (Statins)

A
  • Rosuvastatin (Crestor)
  • Atorvastatin (Lipitor)
  • Simvastatin (Zocor)
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13
Q

MOA of HMG-CoA Reductase Inhibitors (Statins)

A
  • inhibit HMG-CoA Reductase (the rate limiting step of cholesterol synthesis)
  • compensatory increase in LDL receptors
  • best given in evening (diurnal pattern of cholesterol synthesis)
  • *they inhibit HMG-CoA Reductase in the liver so the liver stops making cholesterol. LDL receptors on surface of liver are up-regulated, so it takes cholesterol from blood and delivers it back to the liver
  • this is a way to remove cholesterol from the periphery
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14
Q

Decrease HMG-CoA Reductase Inhibitors (Statins)

A
  • drug of first choice for most patients with risk for coronary heart disease
  • decrease LDL levels (modest HDL increase)
  • also decreases triglyceride levels
  • patients with coronary after disease - decreased cardiac morbidity, mortality, reduced incidence of stroke
  • benefits seen with initial high or normal cholesterol
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15
Q

Some adverse effects of HMG-CoA Reductase Inhibitors (Statins)

A
  • well tolerated
  • CI in pregnancy
  • myalgia (muscle weakness)
    • may increase with cyclosporine, vibrates, or niacin
    • monitor creatine kinase levels
  • increase in plasma aminotransferase by 3x in less than 2%
    • symptomatic hepatitis rare
  • first pass metabolism - CYP3A4
    • avoid CYP3A4 inhibitors (grapefruit juice) with some statins

Questionable adverse effects:

  • renal dysfunction
  • behavioral and cognitive
  • diabetes
  • neuropathy
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16
Q

HMG-CoA Reductase Inhibitors (Statins) are metabolized by ____

A

CYP3A4

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17
Q

HMG-CoA Reductase Inhibitors (Statins) are partially pumped out by ??

A

P-glycoprotein

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18
Q

How does grapefruit juice affect the bioavailability of atorvastatin?

A

increases it to 200%

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19
Q

How does grapefruit juice affect the bioavailability of simvastatin?

A

increases it to 1500%

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20
Q

How does grapefruit juice affect the bioavailability of rosuvastatin?

A

no change

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21
Q

The majority of statin LDL-C efficacy is with the _____ dose

A

starting

*this just means that increasing the dose does not increase the therapeutic effect that much

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22
Q

Ezetimibe is an example of ??

A

Cholesterol Absorption Inhibitor

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23
Q

How do cholesterol absorption inhibitors (ex. ezetimibe) work?

A

inhibit cholesterol transport protein NPC1L1

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24
Q

Give some general points about Ezetimibe (cholesterol absorption inhibitors)

A
  • inhibit dietary and biliary cholesterol absorption
  • work at intestinal brush border
  • no effect on triglycerides & fat soluble vitamins
  • inhibits a cholesterol transport protein (NPC1L1)
  • get reflex increase in cholesterol synthesis
25
Q

How much does Ezetimibe (cholesterol absorption inhibitors) lower cholesterol when used alone?

A

15-20%

26
Q

Ezetimibe (cholesterol absorption inhibitors) may be useful when added to a ____

A

statin

  • allow lower dose of statin
  • with combination - possible greater elevations of transmainases (than statins alone)
27
Q

Side effects of ezetimibe (cholesterol absorption inhibitors)

A
  • myalgia (muscle weakness)
  • hepatitis
  • rhabdomyolysis
  • acute pancreatitis
28
Q

List some bile acid binding resins

A
  • Cholestyramine (Question)
  • Colestipol (Colestid)
  • Colesevelum (Welchol)
29
Q

Explain how bile acid binding resins work

A

95% of bile acid is reabsorbed, so bile acid binding resins prevent it from being reabsorbed in the liver

*to produce new bile acids, liver must:
take up cholesterol (increase LDL receptors) and/or synthesize de novo cholesterol

30
Q

List some general points about bile acid binding resins

A
  • useful in mild to moderate elevated LDL levels
  • effective with statins or nicotinic acid in high LDL levels
  • anion exchange resin - not absorbed from gut
31
Q

Adverse effects of bile acid binding resins?

A
  • may increase VLDL levels
  • decrease absorption of fat soluble vitamins (vitamin K deficiency a problem)
  • nausea, constipation and bloating
  • unpleasant taste and texture
  • absorption of drugs altered (positive, negative, neutral)
    i. e. digitalis, thiazides, warfarin, aspirin, etc.
32
Q

What is a good additive combination in lowering cholesterol?

A

statin + ezetimibe

33
Q

Why do you combine a statin (HMG-CoA reductase inhibitor) with ezetimibe?

A

1) Ezetimibe decreases cholesterol uptake in gut but compensatory increase in cholesterol synthesis in liver
2) HMG-CoA reductase inhibitor blocks this increased synthesis in liver

34
Q

What is the dose for the Ezetimibe/Simvastatin combo?

A

10mg/40mg

35
Q

How does ezetimibe work?

A

Decreases cholesterol uptake in the gut

36
Q

How do statins (HMG-CoA Reductase inhibitors) work?

A

blocks cholesterol synthesis in the liver

37
Q

Add-on to statin therapy:

What % decrease of LDL-C with double statin dose

A

-6%

38
Q

Add-on to statin therapy:

What % decrease of LDL-C with ezetimibe 10 mg?

A

-15 to -30%

39
Q

Add-on to statin therapy:

What % decrease of LDL-C with Niacin 2 g?

A

-14%

40
Q

Add-on to statin therapy:
What % decrease of LDL-C with bile acid binding agent?
(cholestipol 2 scoops 6g)
(cholestyramine 2 scoops 8g)

A

-12%

41
Q

Add-on to statin therapy:

What % decrease of LDL-C with fenofibrate 145 mg?

A

-6 to +4%

42
Q

Add-on to statin therapy:

What % decrease of LDL-C with gemfibrozil 600 mg BID?

A

+7%

43
Q

What are the patient-related causes of failure to achieve LDL-C target?

A
  • poor adherence to treatment
  • high baseline LDL-C
  • high cholesterol diet
  • high cholesterol absorption
  • variable statin response
  • inability to tolerate (higher-dose) statins
44
Q

Describe the newest therapy for patients that can’t meet target levels of LDL under current therapy

A

Targeting the LDL receptor: PCSK9 (pro protein converts subtilizing kevin type 9) - targets the LDL receptor for degradation

Inject human monoclonal antibody to PCSK9 to increase LDL receptors on liver (Alirocumab) or (Evolocumab)

45
Q

Describe the role of PCSK9 in the regulation of LDL receptor expression

A
  • PCSK9 combines with LDL particle and LDL-Receptor to form LDL-R/PCSK9 complex
  • endocytosis occurs
  • clarithrin-coated vesicle formes
  • Lysosome lyses the complex

*see slide 27

46
Q

Describe the impact of PCSK9 antibody on LDL Receptor Expression

A
  • PCSK9 combines with LDL particle and LDL-Receptor to form LDL-R/PCSK9 complex
  • endocytosis occurs
  • clarithrin-coated vesicle formes
  • endosome forms
  • LDL particles gets lysed by the lysosome
  • KEY DIFFERENCE: LDL-R gets recycled and goes back to the surface

*see slide 28

47
Q

____ is the reverse cholesterol transport (takes cholesterol from the periphery to the liver)

A

HDL

48
Q

Describe some possible sites to decrease triglycerides

A
  • reduce the amount of triglycerides in our diet (reduce dietary fat)
  • increase activity of lipoprotein lipase
  • reduce VLDL that are generated by the liver
49
Q

Describe dietary fibre as a non-pharmacological approach to decrease cholesterol

A
  • it is an investable plant residue (ground inner husk)
  • water soluble oats, beans fruit)
  • unknown mechanism of action
50
Q

Other benefits of dietary fiber?

A
  • increases bulk of stool
  • good for constipation
  • decreases colonic cancer
51
Q

Problems and adverse effects of dietary fiber

A
  • need large amounts of fiber
  • gaseous distention
  • long term effect and safety unknown
52
Q

What are 2 examples of fibric acid derivatives - fibrates?

A

Fenofibrate (Tricor)

Gemfibrozil (Lopid)

53
Q

What do Fenofibrate and Gemfibrozil do? (fibric acid derivatives)

A

primarily decrease triglycerides and may increase HDL

incidence of death from CHD, nonfatal MI and stroke is decreased

54
Q

Mechanism of fibrates?

A
  • increased VLDL clearance (increase lipoprotein lipase activity)
  • decreased VLDL secretion (from the liver?)
55
Q

Adverse effects of Fibrates?

A
  • flu-like (muscle cramps, tenderness, stiff, weak) (increased myopathy when combined with statins)
  • myopathy = disease of muscle tissue
  • avoid in hepatic or renal dysfunction
  • may potentiate oral anticoagulants and hypoglycaemic agents
  • increases cyclosporine clearance - transplant rejection?
  • use with caution if increased risk of biliary tract disease (women, obese patients, first nations)
56
Q

Describe the actual mechanism of action of fibrates

A

PPARalpha = peroxisome proliferator activated receptor alpha

  • fibrates attack PPARalpha
  • PPARalpha binds with RXR
  • activates LPL (lipoprotein lipase)
57
Q

Generally describe Nicotinic Acid (Niacin)

A
  • water soluble vitamin B3 nicotinic acid (NOT nicotinamide)
  • low dose increase HDL levels
  • higher dose decreases VLDL levels and decreases triglycerides
  • may decrease LDL levels
58
Q

Mechanism of action of Nicotinic Acid (Niacin)

A
  • decreased hepatic VLDL production
  • activates Niacin receptors in adipocytes
  • decreases cAMP
  • decreases TG hydrolysis
  • less fatty acid in circulation to be taken up by liver and converted to TG and then secreted as VLDL
  • increased VLDL clearance (increased lipoprotein lipase activity)
  • effective at decreasing triglycerides and increasing HDLs
59
Q

Adverse effects of Niacin?

A
  • limited by poor tolerability
  • skin flushing and pruritus
  • acute (7-10 days) and aspirin blunts
  • exacerbation of peptic ulcer
  • may increase aminotransferase or alkaline phosphatase
  • monitor liver function regularly (hepatotoxic)
  • glucose intolerance

Pharmacology B (21 decks)

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