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SUM '20 - Pharm II > Week 2 Lipid Lowering (everything) > Flashcards

Week 2 Lipid Lowering (everything) Flashcards

1
Q

Lipoprotein classification is based on

A

relative density

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2
Q

Name the 5 Lipoprotein classes:

A
  1. Chylomicrons 2. Very Low-density lipoproteins (VLDL) 3. Intermediate-density Lipoproteins (IDL) 4. Low-Density lipoproteins (LDL) 5. High-Density lipoproteins (HDL)
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3
Q

Exogenous Lipoprotein metabolism

A

bile emulsifies dietary fats, cholesterol, and lipid soluble vitamins

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4
Q

Endogenous lipoprotein metabolism

A

hepatic cholesterol synthesis and its distribution to the peripheral tissues

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5
Q

Exogenous pathway small intestines:

A

bile emulsifies dietary fat and cholesterol

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6
Q

Exogenous Pathway: Pancreas:

A

lipase excreted by the pancrease Hydrolyzes triglycerides

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7
Q

Exogenous pathway: Intestinal Endothelium

A

takes up the products (from small intestine and pancreas) by endocytosis and packages lipids into large chylomicrons, which then enter the lymphatic system

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8
Q

Process in which the intestinal endothelium takes up byproducts of SI and pancreas

A

endocytosis

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9
Q

exogenous pathway after endocytosis, what happens?

A

lipids are packaged into large chylomicrons and enter the lymphatic system

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10
Q

Exogenous pathway in order: Chylomicrons →

A

Chylomicrons → travel through thoracic duct → enter blood stream → interaction with lipoprotein lipase (LPL) in vascular endothelial cells → yields glycerol and free fatty acids

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11
Q

these can be utilized by peripheral tissues for fuel or storage

A

glycerol and free fatty acids

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12
Q

During the Exogenous metabolism pathway, Chlomicrons shrink and become

A

chylomicron remnants

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13
Q

Chylomicron remnants →

A

Remnants → transport to liver → taken up by hepatocytes via endocytosis → then hydrolyzed

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14
Q

Endogenous Pathway: What process happens in the liver? Hepatocytes do what?

A

Hypatocytes synthesize: -Cholesterol -Lipids -Proteins -which are assembled into VLDL and excreted into the blood stream

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15
Q

Endogenous Pathway: Cholesterol, Lipids , and proteins synthesized and assembled into

A

VLDL (very low density lipoproteins) and excreted into the blood stream

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16
Q

Endogenous Pathway: Endothelial cell LPL hydrolyzes the

A

fats in VLDL particles -which then shrink form IDL and LDL

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17
Q

Endogenous Pathway: What particles contain most of the cholesterol in the plasma?

A

LDL particles

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18
Q

Endogenous Pathway: LDL particles are cleared from the blood by

A

binding to LDL receptors (LDL-R) on hepatocytes

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19
Q

Endogenous Pathway: Essential cofactors of the hydrolysis of VLDL are: (2)

A

Apoproteins C and E

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20
Q

Endogenous Pathway: Apoproteins C and E are contributed by which particles?

A

HDL particles

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21
Q

Endogenous Pathway: What also transfers ApoC-II to chylomicrons in the exogenous pathway?

A

HDL

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22
Q

HDL is also responsible for reverse

A

reverse cholesterol transport

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23
Q

Explain reverse cholesterol transport:

A

excess cholesterol is delivered from the peripheral tissues to the liver for excretion in the bile *HDL responsible for this

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24
Q

A minority of lipid disorders arise from:

A

-genetic defect in lipoprotein metabolism

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25
Q

When may genetic lipoprotein metabolism defects appear?

A

pediatric or young adults

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26
Q

Familial hypercholesterolemia arises from:

A

a defect in the gene for LDL-R

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27
Q

In Familial hypercholesterolemia HETERozyogotes for this defect experience accelerated

A

atherosclerosis *and represent 1 in 500 persons

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28
Q

in Familial hypercholesterolemia, HOMOzygotes are more rare:

A
  • Total LDL cholesterol levels 4 x normal - extreme propensity for Atherosclerosis
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29
Q
  • Total LDL cholesterol levels 4 x normal - extreme propensity for Atherosclerosis lipid disorder?
A

HOMOzyogote familial hypercholesterolemia

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30
Q

atherosclerosis represented in ~ 1 in 500 persons Lipid disorder?

A

Familial hypercholesterolemia HETERozyogotes

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31
Q

Secondary Causes that hyperlipidemia may arise from include:

A
  1. obesity 2. DM 3. Alcohol abuse 4. Hypothyroidism 5. Glucocoriticoid excess 6. Hepatic or Renal Dysfunction
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32
Q

Most cases of hyperlipidemia in adults arise from

A

combo of: -genetics -environment (poor diet /lack of exercise) -Secondary causes

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33
Q

Elevated LDL is associated with

A

Increase R/O CV Disease

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34
Q

Elevated HDL reduces:

A

Reduces risk of atherosclerosis and CV events

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35
Q

How does increased HDL help reduce risk of atherosclerosis and CV events?

A

HDL is critical in role in reverse cholesterol transport

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36
Q

Decreased plasma concentrations of TOTAL and LDL with medication reduces

A

the risk of CV events in pts WITH and WITHOUT CAD

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37
Q

Hypertriglyceridemia is known to cause:

A

pancreatitis

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38
Q

Hypertriglyceridemia has a casual relationship with

A

atherosclerosis *need to clarify this point in the ppt

Flood, pg 542- the casual relationship of Hypertriglyceridemia to atherosclerosis is less well established

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39
Q

Safety and efficacy of statins

A

are well established

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40
Q

3-hydroxyl-3-methlyglutaryl coenzyme A reductase [HMG-CoA reductase] inhibitors

A

AKA Statins

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41
Q

Statin use guidelines are set by:

A

-American College of Cardiology (ACC) -American Heart Association (AHA)

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42
Q

Statin guidelines no longer recommend:

A
  1. target reductions of TOTAL or LDL cholesterol 2. the use of other drugs other than statins
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43
Q

the mainstay of tx for hyperlipidemia

A

Statins

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44
Q

Table 23-2 Statin Benefit Groups

A

[add image]

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45
Q

Table 23-3 Drugs for Tx of Hyperlipidemia

A

[add image]

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46
Q

treatment with statins results in:

A

↓ LDL by 20% - 60%

↑HDL by 10%

↓ Triglycerides 10% - 20% in statin treated pts

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47
Q

Down and dirty MOA of statins

A

combined effect of ↓ cholesterol synthesis and ↑ LDL uptake by liver

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48
Q

Statin drugs: examples (6)

A
  • Atorvastatin
  • Fluvastatin
  • Lovastatin
  • Pravastatin
  • Simvastatin
  • Rosuvastatin
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49
Q

how do statin drugs reduce cardiac events?

A
  • Lowering LDL
  • Stabilize existing atherosclerotic plaques
  • statis may be pleiotropic (producing more than one effect) including anti-inflammatory, antioxidant and vasodilatory properties
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50
Q

CV uses/considerations for statin drugs

A
  • lowers cardiac events (mortality from MI-CVA-PVD) in pts with or without atherosclerosis
  • benefits coronary stenosis (native vessel or graft)
  • Acute coronary syndrome
  • early initiation follow acute MI is recommended
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51
Q

Atorvastatin, Fluvastatin & Rosuvastatin

A

•Completely synthetic compounds.

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52
Q

Lovastatin, Simvastatin & Pravastatin either naturally or synthetically originate from what?

A
  • Aspergillus terreus
  • lovastatin naturally ocurring
  • simvastatin & pravastatin synthetically derived
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53
Q

which statins are pro drugs

A

Lovastatin, Simvastatin

require metabolism to the open β-hydroxyl acid form to be pharmacologically active

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54
Q

which statins are administerd as active β-hydroxyl acid form

A

atorvastatin, fluvastatin & pravastatin

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55
Q

what can decrease the absorption of statins

A

bile acid-binding resins

56
Q

which statin is efffected by food intake

A

lovastatin: food intake increases plasma concentrations (has minimal effect on other statins)

57
Q

which statin is not highly protein bound?

A

pravastatin

58
Q

what is unique regarding pravastatins metabolims

A

•only statin that does not undergo extensive metabolism by Hepatic P450 enzymes

59
Q

elimination time of statins

except atorvastatin

A

1 - 4 hours

elimination time of atorvastatin is 14 hours

60
Q

which statin has the longest elimination time

A

atorvastatin: 14 hours

61
Q

what is uniqe about excretion of atorvastatin and fluvastatin

A

•minimal renal excretion and may not require renal dose adjustments

62
Q

which 3 statins may need dose adjustments for renal patients

A

Pravastatin and to a lesser extent Lovastatin and Simvastatin

63
Q

how long do the pharmacokinetic effects of statins last

A

•24 hours despite short elimination half-times

64
Q

what patients would you not expect to be on statins due to a negative characteristic?

A

Pregnant patients: statins are teratogenic

65
Q

what is the most common intense side effect of Niacin

A

intense prostagladin induced cutaneous flushing in 10% of patients

66
Q

what can be administered 30 minutes before ingestion of niacin to decrease flushing

A

ASA

67
Q

larges doses of Niacin produce

A

Hepatic dysfunction, jaundice

68
Q

name 3 other seemingly general side effects of niacin

A

ABD pain, N/V/D, Malaise

69
Q

in non dibetic patients on niacin what may occur

A

hyperlycemia and abnormal glucose tolerance

70
Q

what disease process can be reactivated by niacin

A

PUD

71
Q

This patient is complaining of orthrostatic hypotension associated with his antihypertensive drugs and myopathy associated statins.- what drug is he taking

A

Niacin

72
Q

how does niacin worsen gout

A

increased concentrations of uric acid in plasma and increased incidence of gouty arthritis

73
Q

Lomitapide - experimental and emerging agents- trials in patients with genetic lipid disorders has shown what favorable reductions

A

LDL and Triglycerides

74
Q

does omega 3 fatty acids fish oil prevent heart disease

A

•No evidence prevents heart disease.

75
Q

omega 3 is what type of fatty acid

A

unsaturated mega-3 fatty acid

76
Q

what is the primary effect of omega 3 fatty acids fish oil

A

•Primary effect of this fatty acid is to decrease plasma concentration of triglycerides. Variable effect on plasma LDL

77
Q

do we stop fish oil due to caogulation issues prior to surgery

A

No evidence to support stopping fish oil due to potential coagulation issues

78
Q

EZETIMIBE

A

•Relatively new. Selective inhibitor of cholesterol absorption leading to a secondary upregulation of LDL-R

79
Q

how does ezetimibe inhibit cholesterol absorption

A

•Cholesterol absorption is inhibited due to the disruption of a complex between annexin-2 and cavolin-1 proteins in the small intestines

80
Q

LDL and HDL effects of Ezetimibe

A
  • ↓ LDL by 8-22%; Negligible effect on HDL
  • Can potentiate effects of statins by 17%
81
Q

fibrates-Clofibrate: increase in noncardiovascular mortality-due to

A

due to low plasma cholesterol concentrations

82
Q

clofibrate: Much of the increased mortality at very low plasma concentrations of cholesterol may be attributable to specific diseases, which decrease cholesterol concentrations…what does this predispose patients to?

A

which predispose pts to hemorrhagic stroke, particularly when systemic hypertension is present.

83
Q

what are the most effective drugs for decreasing plasma concentration of triglycerides

A

FIBRATES

84
Q

post op when are fibrates restarted

A

after well hydrated and able to ingest PO meds

85
Q

name 3 fibrate drugs

A
  • Gemfibrozil
  • Fenofibrate

Bezafibrate:

86
Q

original fibric acid drug, no longer drug of choice d/t concerns of increased noncardiovascular adverse events

A

Clofibrate

87
Q

Fibrates provide a dose dependent

what % decrease in plasma triglycerides

what % increase in HDL

effect on LDL

A
  • 40-50% decrease in plasma triglycerides
  • 10-35% increase in HDL
  • Effect on LDL is variable
88
Q

gemfibrozil protein binding

elimination half time

% unchanged in the urine

A

99%

15 hour elimination half time

70% unchanged in urine

89
Q

which fibrate is a Prodrug

A

Fenofibrate

90
Q

fenofibrate- how do we increase absorption

A

Absorption increased when taken with food.

91
Q

fenofibrate elimination half time

A

20hrs

92
Q

fenofibrate what plasma concentrations increase

A

Increased plasma concentrations of liver transaminase enzymes are more likely to occur with fenofibrate than other fibrates.

93
Q

how is fenofibrate hydrolyzed

A

esterases to active metobolite fenofibric acid

94
Q

fenofibric acid (active metabolite) is metabolized by

A

conjugation with glucuronic acid that undergoes extensive renal excretion

95
Q

fenofibrate most common side effect

A

Gi upset, abd pain, headache

96
Q

this medication has increased cholesterol content of bile (lithogenicity) and may increase formation of gallstones

A

Gemfibrozil: ***test

97
Q

Gemfibrozil administered with statins (especially lovastatin) have what increased risk

A

; Increase risk of myopathy and rhabdomyolysis when given with statins especially lovastatin.

98
Q

gemfibrozil +warfarin=what problem?

A

Anticoagulant effect of warfarin is potentiated. Prudent to avoid in renal and hepatic disease.

99
Q

lomitapide side effects

A

elevated liver enzymes

100
Q

lomitapide MOA

A

inhibitor of microsomal triglyceride transfer protein, thought to be important for the production of chylomicrons in the intestine and VLDL by hepatocytes.

101
Q

mipomersen -experimental and emerging agents- has been recently approved for the treatment of patients with..

A

homozygous familial hyperlipidemia.

administered via weekly sub q injection - substantial decreases in triglycerides.

102
Q

Most common complaints with Statin use?

A

GI, Fatigue, Headache.

103
Q

Most common and rare side effects with Statin use?

A

•Range from simple myalgias to myositis with mild creatine kinase (CK) elevation to life-threatening rhabdomyolysis (>10-fold elevation of CK)

104
Q

What two side effects from Statin use is considered rare?

A

Myositis and rhabdomyolysis are rare.

105
Q

What side effect is reported in 1/3 of Statin users?

A

Myalgias (muscle aches)

106
Q

What drug is responsible for decreasing cholesterol synthesis and the formation of ubiquinone (coenzyme Q10) which is important for mitochondrial function and cell membrane integrity?

A

Statins

107
Q

It is thought that Statins may possibly inhibit HMG-CoA reductase, what would this cause?

A

Myotoxicity

108
Q

What are some examples of CYP3A4 inhibitors?

A

•Coumadin, Protease Inhibitors (HIV), Macrolide Abx, and Azole Antifungals.

109
Q

What two Statins specifically have myopathy as a frequent side effect?

A

Simvastatin and Lovastatin

110
Q

what metabolizes Simvastatin and Lovastatin?

A

Metabolized by CYP3A4

111
Q

If Simvastatin and Lovastatin are metabolized by CYP3A4, then if they are given with meds like coumadin, protease inhibitors, Macrolide Abx, and Azole Antifungals, what may happen?

A

The concentration of Simvastatin or Lovastatin will be higher for a longer amount of time bc the drugs listed to be given with the statins inhibit CYP3A4.

112
Q

What two statins are Metabolized by CYP2C9 and have lowest rate of events compared to statins metabolized by CYP3A4?

A

Fluvastatin and rosuvastatin

113
Q

Have Anesthesia drugs been shown to increase incidence of statin induced myopathy?

A

No

114
Q

What medication would you use to treat lipid disorders that have a primarily abnormal increase in plasma LDL cholesterol concentration with a normal or near normal triglyceride level?

A

Bile acid resins

115
Q

What drugs are included in the class of Bile acid resins?

A
  • Colesevelam
  • Cholestyramine
  • Colestipol
116
Q

Bile acid resins are tolerated well and have a low level of what?

A

low level of toxicity

117
Q

What type of cholesterol issues would you have if you were to be placed on a Bile acid resin as treatment?

A

If you have abnormally high LDL but your triglyceride level is normal.

118
Q

What form do bile acid resins come in? (liquid, inhaled, powder, shot etc?)

A

•Are powders and must be rehydrated before ingestion

119
Q

True or false:

Bile acide resins have systemic absorption?

A

False, •No systemic absorption of these resins

120
Q

How do Bile acid resins work?

A

•Bile acid resins bind bile in the intestine, interrupting enterohepatic circulation and increasing fecal excretion that increase hepatic bile acid synthesis from cholesterol stores.

121
Q

Based on how Bile acid resins work, what types of cholesterol do they increase and/or decrease?

A

They increase the production of hepatic LDL-R and increases uptake of LDL cholesterol from the blood, lowering plasma concentrations of LDL. HMG-CoA reductase activity increases as well.

122
Q

In simple terms what do Bile acid resins do to LDL?

A

Has the liver take out all the little LDL’s from the blood stream and get rid of em

123
Q

If Bile acid resins are administerd as a solo therapy they are responsible for two main things?

A
  • decrease plasma concentrations of LDL by 15-30%
  • Plasma concentrations of triglycerides may increase 5-20% owing to increased productions of VLDLs.
124
Q

With the use of Bile acid resins alone, what type of cholesterol level will rise?

A

•Plasma concentrations of triglycerides may increase 5-20% owing to increased productions of VLDLs.

125
Q

What are two common complaints with bile acid resins?

A

Palatability and Constipation

126
Q

What should you be making sure you have enough of if you are taking bile acid resins?

A

high fluid intake bc they can cause constipation.

127
Q

How long before and/ or after the administration of Cholestyramine (bile acid resin) should you give other drugs?

A

other drugs should be give 1 hour before or 4 hours after the administration of Cholestyramine.

128
Q

Which Bile acid resin has fewer GI side effects and thus is approved for adolescents with familial hypercholesterolemia?

A

Colesevelam

129
Q

What negative ion and absorption issues are associated with the use of Cholestyramine?

A

a chloride form of an ion exchange resin thus hyperchloremic acidosis can occur especially in younger and smaller pts (where relative doses are larger); Impairs absorption of fat-soluble vitamins and other meds may be impaired;

130
Q

What is Niacin?

A

Niacin: Water soluble B complex vitamin that inhibits synthesis of VLDLs in liver

131
Q

How does Niacin work? (MOA)

A

Unknown

132
Q

Even though the MOA of Niacin is unknown, we do know that it works by doing what? (think fatty stuff)

A

•Niacin inhibits free fatty acids from adipose tissue and increases the activity of lipoprotein lipase

133
Q

What all in realation to cholesterols does Niacin actually improve?

A
  • Decrease in plasma LDL 15-30%
  • Decrease in Triglycerides 20-50%
  • Increase in HDL 20-30%
  • No change in synthesis of cholesterol
  • Does not alter excretion of bile acids
134
Q

Does Niacin undergo extensive hepatic first pass metabolism?

A

YES

135
Q

What body system readily absorbs Niacin?

A

GI tract

136
Q

Tell me about the metabolism of Niacin and it’s metabolites?

A
  • Primary Route of Metabolism is Methylation to N-methyl-nicotinamide
  • Also undergoes conjugation with glycine to produce nicotinuric acid
137
Q

what body system is responsable for the elimination of niacin

A

•Metabolites undergo renal excretion and at high doses, niacin undergoes renal excretion unchanged.

SUM '20 - Pharm II (30 decks)

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