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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
How much does Ezetimibe (cholesterol absorption inhibitors) lower cholesterol when used alone?
15-20%
26
Ezetimibe (cholesterol absorption inhibitors) may be useful when added to a ____
statin - allow lower dose of statin - with combination - possible greater elevations of transmainases (than statins alone)
27
Side effects of ezetimibe (cholesterol absorption inhibitors)
- myalgia (muscle weakness) - hepatitis - rhabdomyolysis - acute pancreatitis
28
List some bile acid binding resins
- Cholestyramine (Question) - Colestipol (Colestid) - Colesevelum (Welchol)
29
Explain how bile acid binding resins work
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
List some general points about bile acid binding resins
- 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
Adverse effects of bile acid binding resins?
- 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
What is a good additive combination in lowering cholesterol?
statin + ezetimibe
33
Why do you combine a statin (HMG-CoA reductase inhibitor) with ezetimibe?
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
What is the dose for the Ezetimibe/Simvastatin combo?
10mg/40mg
35
How does ezetimibe work?
Decreases cholesterol uptake in the gut
36
How do statins (HMG-CoA Reductase inhibitors) work?
blocks cholesterol synthesis in the liver
37
Add-on to statin therapy: | What % decrease of LDL-C with double statin dose
-6%
38
Add-on to statin therapy: | What % decrease of LDL-C with ezetimibe 10 mg?
-15 to -30%
39
Add-on to statin therapy: | What % decrease of LDL-C with Niacin 2 g?
-14%
40
Add-on to statin therapy: What % decrease of LDL-C with bile acid binding agent? (cholestipol 2 scoops 6g) (cholestyramine 2 scoops 8g)
-12%
41
Add-on to statin therapy: | What % decrease of LDL-C with fenofibrate 145 mg?
-6 to +4%
42
Add-on to statin therapy: | What % decrease of LDL-C with gemfibrozil 600 mg BID?
+7%
43
What are the patient-related causes of failure to achieve LDL-C target?
- poor adherence to treatment - high baseline LDL-C - high cholesterol diet - high cholesterol absorption - variable statin response - inability to tolerate (higher-dose) statins
44
Describe the newest therapy for patients that can't meet target levels of LDL under current therapy
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
Describe the role of PCSK9 in the regulation of LDL receptor expression
- 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
Describe the impact of PCSK9 antibody on LDL Receptor Expression
- 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
____ is the reverse cholesterol transport (takes cholesterol from the periphery to the liver)
HDL
48
Describe some possible sites to decrease triglycerides
- 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
Describe dietary fibre as a non-pharmacological approach to decrease cholesterol
- it is an investable plant residue (ground inner husk) - water soluble oats, beans fruit) - unknown mechanism of action
50
Other benefits of dietary fiber?
- increases bulk of stool - good for constipation - decreases colonic cancer
51
Problems and adverse effects of dietary fiber
- need large amounts of fiber - gaseous distention - long term effect and safety unknown
52
What are 2 examples of fibric acid derivatives - fibrates?
Fenofibrate (Tricor) | Gemfibrozil (Lopid)
53
What do Fenofibrate and Gemfibrozil do? (fibric acid derivatives)
primarily decrease triglycerides and may increase HDL incidence of death from CHD, nonfatal MI and stroke is decreased
54
Mechanism of fibrates?
- increased VLDL clearance (increase lipoprotein lipase activity) - decreased VLDL secretion (from the liver?)
55
Adverse effects of Fibrates?
- 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
Describe the actual mechanism of action of fibrates
PPARalpha = peroxisome proliferator activated receptor alpha - fibrates attack PPARalpha - PPARalpha binds with RXR - activates LPL (lipoprotein lipase)
57
Generally describe Nicotinic Acid (Niacin)
- 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
Mechanism of action of Nicotinic Acid (Niacin)
- 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
Adverse effects of Niacin?
- 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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