Statins And GI Flashcards

1
Q

PCSK9 Inhibitors

A

Decreases LDL by 60%
Side effects:
Hypersensitivity rxs, possibly neurocognitive events

Evolocumlab
Alirocumab

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2
Q

Decreasing incidence of heart disease

A

the longer and lower the reduction in circulating LDL-C, the lower the incidence of CHD

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3
Q

Lipoproteins in the gut versus liver

A
Gut = chylomicrons - LDL and TG
Liver = VLDL - LDL and TG
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4
Q

Coronary Artery Disease Risk Factors

A
High TG
High cholesterol
High BP
Smoking
Gender/age/family hx

Drugs that decrease LDL-cholesterol -> heart disease

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5
Q

What is the RLS in cholesterol synthesis?

A

Enzyme HMG CoA reductase

HMG CoA -> mevalonate

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6
Q

What do LDL receptors in the liver control?

A

The production and catabolism of plasma LDL

VLDL -> IDL -> LDL

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7
Q

SREBP

A

Transcription factor = the master regulator of cholesterol levels in cells

In a low-cholesterol diet = SREBP is ACTIVE
In a high-cholesterol diet = SREBP is INACTIVE

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8
Q

When SREBP is active under conditions of low cholesterol diet…

A

Increase in cholesterol biosynthesis
Increase in receptor mediated LDL-endocytosis from plasma
Decrease plasma LDL

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9
Q

When SREBP is inactive under conditions of low cholesterol diet…

A

Decrease in LDL biosynthesis
Decrease in LDL receptors
Plasma LDL remains high

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10
Q

Statins are best tolerated for treating:

A

Dyslipidemia

HMG CoA reductase inhibitors (competitive inhibitors)

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11
Q

Statin function:

A

Inhibit cholesterogenesis
Increased expression of LDL receptor
Increased removal of LDL from the blood (levels decrease 20-55%)
Decreased VLDL production

TG levels decrease
HDL levels slightly increase

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12
Q

What part of the LDL molecule is recognized by the LDL receptor?

A

ApoB protein on the LDL

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13
Q

SLCO1B1

A

Gene that encodes for OATP1B1

When mutated, it reduces hepatic uptake of simvastatin acid

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14
Q

PCSK9

A

Proprotein convertase substilsilin/kexin

Degrades the LDLR

The antibody to PCSK9 (PCSK9-inhibitor) allows the LDLR to be recycled.

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15
Q

What is commonly used with statins to reduce LDL levels in plasma?

A

Evolucumab (PCSK9 inhibitor)

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16
Q

Ezitimibe

A

Cholesterol absorption inhibitor in the intestine

When combined with statins = 50-60% decrease
Alone = 19%

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17
Q

What does ezitimbe block?

A

NPC1L1 = cholesterol transporter in enterocytes

Inhibits cholesterol and plant sterol absorption.
Decreases delivery of cholesterol to the liver, slightly increases HDL
Increases expression of hepatic LDL receptor
Decreases the cholesterol content of atherogenic particles

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18
Q

Is Ezitimbe well tolerated?

A

Not systemically well tolerated

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19
Q

Resins

A

Also known as BAR - bile acid sequestrant resins

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20
Q

Cholestyramine

A

BAR

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21
Q

Colestipol

A

BAR

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22
Q

Colesevelam

A

BAR

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23
Q

Cholate

A

Bile Salt

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24
Q

Deoxycholate

A

bile salt

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25
Q

Therapeutic uses of BARs

A

Pts with bile salt accumulation must take with meals OR no effect!

Removes digitalis from the GI tract

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26
Q

Familial Hypercholesterolemia

A

Reduction in the number of LDL receptors, therefore LDL accumulates in the plasma

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27
Q

What is the net effect of Bile Acid Sequesterants (Resins)?

A

Decrease in LDL-C levels (2 weeks)
Increases LDL receptors
Increase in BA secretion
Increase in Cholesterol 7Alpha Hydroxylase

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28
Q

What is the mechanism of resins?

A

Bind to the (-) charged bile acids, excreted in stool

HMG-CoA reductase upregulated (this increase in LDL slightly offsets the reduction in LDL)

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29
Q

What increases the effectiveness of a resin?

A

coadministration of a statin, increases effectiveness of resin

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30
Q

What pts should be avoided with administration of a resin?

A

Pts with severe hypertrigylceremia, as HDL-C levels increase 4-5%

Concern is in pts that have >250mg HDL-C levels

Resins taken approx 4hrs before/after use of a statin/ezitimibe

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31
Q

What is the toxicity of a resin?

A

Constipation, bloating = relieved by fiber, psyllium seed

Heartburn
Diarrhea

Rare: malabsorption of folic acid, vitamin K (hypoprothrombinia)

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32
Q

SREBP

A

When active = in situations of low circulating LDL

  • upregulates the receptor to bring more cholesterol into the cell
  • increases cholesterol biosynthesis

When inactive = in situations of high circulating LDL

  • reduces the number of receptors, so not as much cholesterol brought into cell
  • decreases cholesterol synthesis
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33
Q

Statin as a competitive inhibitor of HMG CoA Reductase. Effects?

A

Inhibit cholesterolgenesis
Increase expression of LDL receptor
Increase removal of LDL (VLDL, IDL) from blood
Decrease hepatic VLDL production

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34
Q

Therapeutic Use of Statins

A

Alone or in combination with resins or ezetimibe
▪ Contraindicated in women who are pregnant, lactating or likely to become pregnant (category X, teratogenic)
▪ Some statins approved for use in children homozygous or heterozygous for familial hypercholesterolemia

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35
Q

Toxic Effects of Statins

A

Liver effects

Elevations in serum alanine aminotransferase (ALT) activity (up to 3x normal)

Medication should be discontinued if ALT >3x is persistent or signs of hepatotoxicity present (precipitous decrease in LDL, anorexia, malaise)

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36
Q

Myopathy from Statin use

A

increased incidence of myopathy associated with polymorphisms in gene encoding liver-specific OAT

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37
Q

Drug Interactions of Statins:

A
  • seen when some statins given with other drugs & substances (e.g., grapefruit juice) metabolized by CYP3A4
    CYP3A4 is responsible for degrading Statins, therefore if there are CYP3A4 inhibitors, then plasma levels of statins increase
  • Inhibitors of organic anion transporter (OAT)
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38
Q

Statin uptake by the liver - abrnomalities

A

Genetically impaired activity of organic anion–transporting polypeptide 1B1 (OATP1B1) encoded by SLCO1B1 reduces hepatic uptake of active simvastatin acid
- causing accumulation of simvastatin acid in plasma and an increased risk of myopathy.

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39
Q

How are PCSK9 inhibitors administered?

A

Subcutaneous administration

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40
Q

PCSK9 inhibitors

A

Decrease LDL-C by preventing degradation of the receptor

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41
Q

What BAR tends to not interact with statins?

A

Colesevelam does not appear to interfere with the absorption of most statins.

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42
Q

Peptic Ulcer symptom

A

Pain in gut 2-3 hours postprandial or in the middle of the night

Causes:
NSAID
Helicobaacter pylori (erodes the membrane)

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43
Q

Peptic Ulcer Syndrome by H. Pylori and Treatment

A

Treated with amoxicillin, tetracycline, clarithromycin

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44
Q

GERD

A

Gastroesophageal reflux disease

  • symptoms of mucosal damage produced by gastric contents into the esophagus
  • delayed gastric emptying
  • excess acid production
  • lower esophageal spinchter
  • hiatal hernia
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45
Q

What are the symptoms of GERD?

A

Heartburn (pyrosis) - discomfort leading into neck
Regurgitation
Occurs mainly after fatty meals

Alarm symptoms:

  • dysphagia
  • odynophagia
  • bleeding / wt loss / anemia
  • long duration of symptoms
46
Q

What is the gold standard for monitoring GERD/

A

Ambulatory reflux (pH monitoring)
- trans nasally placed catheter and wireless device attached to distal esophageal mucosa
Collect pH -> 1-4 days with the wireless device

47
Q

Other monitoring of GERD:

A

Esophageal manometry - measures LES spinchcter
Barium Swallowing - detects peptic ulcers
Endoscopy - upper GI exam

48
Q

What is Barrett Syndrome?

A

Abrnormal change in cells that can lead to adenocarcinoma

49
Q

What are some lifestyle modifications for GERD?

A
Elevate head of bed
Decrease Fat Intake
Avoid Acidic Foods - citrus, alcohol, caffeine
Stop Smoking
Avoid recumbency 3 hrs after eating
Lose wt if necessary
50
Q

Surgery for GERD indicated for:

A

Recurrent pulm symptoms
Barrett esophagus
Severe esophagitis
Success = best in pts with <50% and with symptoms that resolve with PPI

51
Q

Tagamet

A

H2 Receptor Antagonist

52
Q

Zantac

A

H2 Receptor Antagonist

53
Q

Pepcid

A

H2 Receptor Antagonist

54
Q

Protonix

A

PPI

55
Q

Prilosec

A

PPI

56
Q

Prevacid

A

PPI

57
Q

Aciphex

A

PPI

58
Q

Nexium

A

PPI

59
Q

Clarithromycin

A

Antibiotic for H. Pylori, which might cause GERD

60
Q

Amoxicillin

A

Anti-biotic for H. Pylori

61
Q

Tetracycline

A

Antibiotic

62
Q

Heartburn 2x/week

A

associated with GERD

63
Q

What is GERD?

A

Mucosal damage produced by abnormal reflux of gastric contents in the esophagus

64
Q

What causes GERD?

A

Excess acid production in stomach
Delayed gastric emptying

  • acid builds up
  • bc of hiatal hernia, changing in resting pressure (incompetent LES), acid enters esophagus
65
Q

Acid Reflux occurs when…

A

LES - pressure is often low

No esophageal pinch in the diaphragm

66
Q

GERD is made worse by…

A

Recumbuncy (reclining)

Occurs mainly after fatty meals

67
Q

Symptoms of GERD

A

Regurgitation

Heartburn (pyrosis) - sterna burning discomfort that radiates towards neck

68
Q

Alarm symptoms of GERD (to worry about complicated disease)

A

Dysphagia (difficulty swallowing)
Odynophagia (painful swallowing)

Bleeding
Wt Loss
Anemia
Long Duration 
No Responses to treatment
69
Q

Can assume a diagnosis of GERD if there is…

A

A symptomatic response to anti secretory therapy with a PPI or H2 Antagonist

If no response to treatment or alarm symptoms present, consider further testing.

70
Q

What is an upper GI exam?

A

Endoscopy

- considered if there is a “complicated disease” or at risk for Barrett’s esophagus

71
Q

What is Barrett’s Esophagus?

A

Abnormal change in cells that can lead to esophageal adenocarcinoma (a lethal form of cancer)

GI Endoscopy done if the pt is at risk for this

72
Q

To confirm Barrett’s esophagus…

A

Biopsy needed

73
Q

What is essential for a diagnosis of GERD?

A

typical esphagitis

a normal endoscopy does not rule out GERD
- possibility of non-erosive reflux disease

74
Q

What is the gold standard for a GERD diagnosis?

A

Ambulatory reflux (pH) monitoring: Carried out if…

  • trial of acid suppression has failed
  • if there is no evidence of mucosal damage on endoscopy

Collection Time:
- 1-4 days with the wireless device

75
Q

Barium Swallow

A

Used to detect GERD

  • limited use in diagnosis
  • useful in detecting peptic strictures
76
Q

Esophageal Manometry

A

Measure LES pressure
Minimal use in diagnosis

Done usually to:
- evaluate peristaltic functioning before antireflux surgery to exclude major motility disorders

77
Q

Treatment options for GERD: Lifestyle Modifications

A
Elevate head while in bed
Decrease fat intake
Avoid acidic foods - 
Stop smoking (as tobacco inhibits saliva and stimulates gastric acid)
Avoid Recumbency 3 hrs after eating
Lose weight if necessary
78
Q

Antacids

A

Shown to provide relief in 20% of patients

- More RAPID response than H2Receptor Antagonists

79
Q

H2 Receptor Antagonists

A

Lower in strength than antacids, yet longer acting

Does not promote healing!

Only approved for relief of occasional heartburn symptoms!

80
Q

Omeprazole

A

Proton Pump Inhibitor

The dose is identical to a 14 day short-term treatment

81
Q

What treatment for GERD suppresses acid?

A

Antacids

82
Q

What do antacids do?

A

Used for heart-burn related symptoms

Most patients used 2x/week

83
Q

Antacids are weak bases that react with…

A

HCl to form salt and water

They reduce acidity and therefore pepsin activity (pepsin is inactive in solutions above 4.0

Most antacids are:
NaHCO3, CaCO3, Mg(OH)2, Al(OH)3

84
Q

What are the side effects of antacid use?

A

Mg2+ can cause diarrhea

Al3+ can cause constipation

85
Q

What secretes gastric acid?

A

Three principal agonists

  • histamine
  • acetylcholine (Ach)
  • gastrin
86
Q

What agonists of gastric acid release bind to ECL cells?

A

Gastrin and Ach bind to ECL cells -> causes a Histamine release

Histamine then binds to H2 receptor on parietal cells -> H+/K+ pump active!!

87
Q

Gastrin and Ach can also bind DIRECTLY to parietal cells…

A

Causing activation of the H+/K+ ATPase

88
Q

Gastric Antisecretory Drugs

A

Inhibit the activity of:

  • histamine
  • Ach
  • proton pump
89
Q

Histamine Receptor Blockers (H2 receptor blockers)

A

Inhibit the binding of histamine to the H2 receptor on parietal cells, thereby DECREASING the acid production in the cell

  • eliminates symptoms in 50% of pts with prescription strength dosing
  • costs lower than PPIs
90
Q

Cimeditidine

A

H2 Receptor Antagonist

AKA tagamet

91
Q

Ranitidine

A

Zantac

H2R antagonist

92
Q

Famotidine

A

Pepcid

H2R Antagonist

93
Q

Cimetidine (Tagamet)

A

H2R antagonist

- contains an arginine-like tail, mimicking the NH2 group in histamine

94
Q

Side effects of Cimetidine

A

Dizziness, drowsiness

Breast development in males

H2R Antagonist

95
Q

Ranitidine (Zantac)

A

Replaced imidazole ring of cimetidine with a FURAN ring

10x more active than Cimetidine!

Rantitidine ran longer than Cimet!

96
Q

Famotidine (Pepcid)

A

FTW (Famotidine is 30x more active than cimetidine)

- Best Buy for the money

97
Q

PPIs and mucosal healing…

A

Provides mucosal healing of esophagitis at 6-8 weeks in 75-100% of cases

More expensive than H2 antagonists

98
Q

PPIs

A

Eliminate symptoms and heal esophagitis more rapidly than other agents

99
Q

Do PPIs exist in active or pro-drug form?

A

PRO DRUG

  • they are converted into the active form under low pH
  • they bind IRREVERSIBLY (covalently) to H/K ATPase, the terminal source of acid (H+) in parietal cells

Single dose inhibits 100% of gastric acid secretion - completely knocks out acid secretion

100
Q

The acidic environment allows conversion of…

A

Pro-drug’s intramolecular activation to the active form

Requires acidic environment

101
Q

Rabeprazole

A

PPI

102
Q

Lansoprazole

A

PPI

103
Q

Pantoprazole

A

PPI

104
Q

Omeprazole aka Prilosec

A

PPI

105
Q

Esomeprazole Mg (Nexium)

A

PPI

106
Q

QD

A

Everyday

107
Q

BID

A

2x daily

108
Q

TID

A

3x daily

109
Q

QID

A

4x daily

110
Q

Treatment options for GERD…

A

PPI (-prazole) + antibiotic

Ranitidine bismuth citrate (RBC) + antibiotic

111
Q

What are the indications of GERD for surgery?

A
  • recurrent symptoms, severe esophagitis, recurrent pulm symptoms, Barrett esophagus

Success is in pts <50 yo

Complications of surgery:

  • obstructive symptoms
  • disruption of vagally-mediated relaxation of LES when swallowing
112
Q

What is the most reliable objective indicator of GERD?

A

Ambulatory pH monitoring