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GI-II, Exam 1 > DSA: Tx of PUD and GERD - SRS > Flashcards

DSA: Tx of PUD and GERD - SRS Flashcards

1
Q

What classes of agents which reduce gastric activity do we need to be aware of?

A
  1. PPI
  2. H2-Receptor Antagonists (H2RAs)
  3. Antacids
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2
Q

Give me 6 PPIs we need to know?

A
  1. Dexlansoprazole (Dexilant)
  2. Esomeprazole (Nexium)
  3. Lansoprazole (Prevacid)
  4. Omeprazole (Prilosec, Zegerid)
  5. Pantoprazole (Protonix)
  6. Rabeprazole (Aciphex)
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3
Q

What are four H2-Receptor Antagonists (H2RAs)?

A
  1. Cimetidine (Tagamet)
  2. Famotidine (Pepcid)
  3. Nizatidine (Axid)
  4. Ranitidine (Zantac)
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4
Q

What are three antacits we covered?

A
  1. Sodium bicarbonate (baking soda, Alka Seltzer)
  2. Calcium carbonate (Tums, Os-Cal)
  3. Magnesium hydroxide/aluminum hydroxide (Mylanta, Maalox)
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5
Q

What are four agents that can be used to provide mucosal protection?

A
  1. Bismuth subcitrate
  2. Bismuth subsalicylate (Pepto-Bismol)
  3. Misoprostol
  4. Sucralfate (Carafate)
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6
Q

What are 4 antibiotics that we use in the treatment of H. pylori?

A
  1. Amoxicillin
  2. Clarithromycin
  3. Metronidazole
  4. Tetracycline
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7
Q

In addition to antibiotic therapy, what else should be employed in the treatment of H. pylori infection?

A

PPI or H2-Receptor Antagonists should be combined with two or more antibiotics

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8
Q

What are three factors that regulate acid secretion through receptor binding on parietal cells?

What type of substance is each?

A

AcH - neuronal

histamine - paracrine

gastrin - endocrine

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9
Q

How do parietal cells play into the secretion of acid?

A
  1. ACh (vagal postganglionic nerves) and gastrin (antral G cells) bind parietal receptors (muscarinic M3 and CCK-B respectively) and stimulate G-protein coupled receptor (GPCR) signaling pathways.
    1. Gq-PLC-IP3-Ca2+ activation leads to an increase in cytosolic Ca2+ which ultimately results in stimulation of acid secretion from H+/K+-ATPase (proton-pump).
    2. H+/K+-ATPase exchanges hydrogen and potassium ions across the parietal cell membrane.
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10
Q

How do enterochromaffin-like cells play into acid secretion?

A
  1. ACh and gastrin also bind gut endocrine cells called enterochromaffin-like (ECL) cells in close proximity to parietal cells which stimulates histamine release.
    1. Histamine released from ECL cells binds H2 receptors on parietal cells and activates the proton-pump via cAMP-dependent GPCR signaling pathways (Gs-adenylyl cyclase-cyclic AMP-PKA).
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11
Q

What is the role of somatostatin in acid secretion?

What produces it?

A

Produced by antral cells, somatostatin inhibits gastric secretion.

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12
Q

What do prostaglandins do in the way of acid regulation in the stomach?

A
  1. Prostaglandins E2 and I2 inhibit the proton-pump by reducing cAMP production (EP3 receptors are GPCRs coupled to Gi on parietal cells).
  2. PGE2 and PGI2 also stimulate production of protective factors (mucus, bicarbonate) by superficial epithelial cells and enhance mucosal blood flow.
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13
Q

What drugs block prostaglandins?

A

NSAIDs - block prostaglandin production leading to more acid, less mucus and less bicarbonate as well as decreased blood flow.

NSAIDs are ulcerogenic and should be avoided in PUD or at least dose reduced.

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14
Q

What lifestyle modifications are adviseabe for patients with acid-peptic diseases?

A
  1. Weight loss in overweight individuals or those who have recently gained weight.
  2. Head of bed elevation if symptoms associated with recumbency.
  3. Avoid meals 2-3 hours before bedtime in those with nocturnal GERD.
  4. Smoking cessation (tobacco effects lower esophageal sphincter).
  5. Cessation of foods that may aggravate reflux (limited or no clinical evidence but recommended if patient experiences symptom relief after cessation): caffeine, coffee, chocolate, spicy foods, acidic foods, high fat content foods.
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15
Q

What are the pharmacotherapy recommendations for GERD at the following levels?

  1. Mild, intermittent symptoms –
  2. Non-erosive disease –
  3. Erosive esophagitis –
A
  1. Mild, intermittent symptoms – antacid or H2RA as needed.
  2. Non-erosive disease – antacid or H2RA (PPI may be required in more severe symptoms).
  3. Erosive esophagitis – PPI for 8 weeks.
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16
Q

Most GERD drugs are category B for pregnancy and safe. One exception exists, what is it?

A

Omeprazole - category C, risk cannot be ruled out

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17
Q

In a pregnant patient with GERD, what are the recommendations for the following?

  1. Mild cases –
  2. Persistent symptoms –
  3. Intractable symptoms/complicated reflux –
A
  1. Mild cases – antacid or sucralfate.
  2. Persistent symptoms – H2RA (ranitidine has most safety data available).
  3. Intractable symptoms/complicated reflux – PPI (lansoprazole or pantoprazole preferred).
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18
Q

PUD presents with mucosal damage secondary to pepsin and gastric acid occurring in the stomach (gastric ulcer) or proximal duodenum (duodenal ulcer). What are some key causes?

A
  1. H. pylori
  2. Chronic NSAID use
  3. Zollinger-Ellison Syndrome
  4. Stress-related mucosal injury (d/t poor perfusion in critically ill patients)
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19
Q

In PUD, what are the pharmacotherapy recommendations for the following?

  1. Initial management –
  2. Duodenal ulcer –
  3. Gastric ulcer –
  4. H. pylori eradication –
A
  1. Initial management – withdrawal of offending/contributing factors, eradication of H. pylori.
  2. Duodenal ulcer – H2RA or PPI for 4 weeks.
  3. Gastric ulcer – PPI for 8 weeks.
  4. H. pylori eradication – Antisecretory agent (PPI preferred) plus at least two antibiotics (see page
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20
Q

In treating GERD and PUD you can approach it from two directions,

  1. Agents which reduce gastric acidity
  2. Agents which promote mucosal defense

Give 3 examples of each.

A
  1. Agents which reduce gastric acidity (PPIs, H2RAs, antacids).
  2. Agents which promote mucosal defense (bismuth compounds, misoprostol, sucralfate).
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21
Q

PPIs include : dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. What is their MOA?

A
  1. inactive prodrugs, lipophilic weak bases diffuse readily across lipid membranes into acidified compartments (parietal cell canaliculus)
  2. from the alkaline intestinal lumen. Rapidly becomes protonated and undergoes conversion to active form which forms a covalent disulfide bond with H+/K+-ATPase, irreversibly inactivating the enzyme.
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22
Q

PPI drugs could be called ideal drugs from a PK perspective, why?

A

ideal drugs from a PK perspective as they have short serum half-lives, concentrated and activated near site of action, and have a long duration of action.

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23
Q

Give me up to 8 therapeutic uses of PPI drugs.

A
  1. GERD
  2. PUD
  3. H. pylori infection
  4. NSAID ulcers
  5. Prevention of re-bleeding
  6. Stress-related mucosal injury
  7. Zollinger-Ellison syndrome
  8. Heartburn
24
Q

What are the ajor ADRs associated with PPI drugs? 5

A
  1. Decreased B12 absorption (can lead to subnormal levels with prolonged therapy)
    1. Anemia
    2. hip fracture
    3. increased pneumonia risk
  2. Increased risk of C. difficile over growth
  3. diarrhea
  4. headache
  5. abdominal pain
25
Q

PPI drugs have some DDI’s based on decreased gastric acidity, which can cause altered absorption of drugs. What are some specific examples Dr. Waller pointed out? 4

A
  1. ketoconazole
  2. itraconazole
  3. digoxin
  4. atazanavir
26
Q
  1. All PPIs metabolized via CYP P450 enzymes (including 2C19 and 3A4) but clinically significant drug interactions are rare due to short t1/2’s. Nonetheless, omeprazole has some DDI’s that were specifically mentioned. What are they?
A

Inhibition of metabolism of:

  • Warfarin
  • diazepam
  • phenytoin
27
Q

What is a drug that the FDA has made a special point of discussing within the context of PPI DDIs?

A

Clopidogril - a prodrug that is activated by CYP2C19. PPIs can reduce activation and decrease the antiplatelet activity of clopidogril.

28
Q

If you must give a patient clopridogrel, what two PPIs are preferred for treatment?

A

Pantoprazole

rabeprazole

29
Q

H2RAs include cimetidine, fomotidine, nizatidine and ranitidine. Their potency varies widely, and they are not as effective as PPIs.

What is their MOA?

A

Competitive inhibition at parietal cell H2-receptors (highly selective, does not affect H1- or H3-receptors) blocks histamine released from ECL cells by gastrin or vagal stimulation.

30
Q

What are H2RAs particularly good at suppressing?

A

Basal secretion rather than meal induced. Also nocturnal acid secretion, which depends largely on histamine.

31
Q

What is the most important thing to control when treating duodenal ulcers?

A

Control of nocturnal acid secretion

32
Q

What are four therapeutic uses for H2RAs?

A
  1. GERD
  2. PUD
  3. NSAID ulcers
  4. Stress-related mucosal injury
33
Q

What are the ADR’s associated with H2RAs?

How about if given IV?

A
  1. Mental status changes
    1. confusion
    2. hallucinations
    3. agitation
  2. Increased risk of nosocomial pneumonia
  3. blood dyscrasias
  4. Bradycardia w/hypotension if given rapid via IV
34
Q

What are some ADR’s specific to cimetidine?

A
  1. gynecomastia or impotence in men
  2. galactorrhea in women.
35
Q

What are some DDIs associated with H2RAs?

A
  1. Competes with creatinine and other drugs (procainamide) for renal tubular secretion.
  2. All H2RAs (except famotidine), inhibit gastric first-pass metabolism of alcohol. Could lead to increased ethanol blood levels but importance of interaction debated.
36
Q

Antacids include sodium bicarbonate, calcium carbonate, and magnesium hydroxide/aluminum hydroxide. What is the MOA of these drugs?

A
  1. weak bases, react with hydrochloric acid (HCl) to form a salt and water. Neutralizes acid and reduces intragastric acidity.
37
Q

Sodium bicarbonate reacts rapidly with HCl to produce carbon dioxide (CO2) and sodium chloride (NaCl). What are some negative consequences to keep in mind here?

A
  1. Formation of CO2 leads to gastric distention and belching. Unreacted alkali (metabolic alkalosis) and NaCl absorption (fluid retention) may pose a risk in patients with heart failure, hypertension, and renal insufficiency. Should not be taken long-term.
38
Q

Calcium carbonate is less soluble and reacts more slowly with HCl to form CO2 and calcium chloride (CaCl2).

What are some negative effects of these drugs to be aware of?

A
  1. May cause belching and metabolic alkalosis. Excessive doses of either sodium bicarbonate or calcium carbonate with Ca2+ containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis. Should not be taken long-term.
39
Q
  1. Magnesium hydroxide/aluminum hydroxide react slowly with HCl to from magnesium chloride (MgCl2) or aluminum chloride (AlCl3) & H2O. No gas is generated so belching does not occur, metabolic alkalosis also uncommon due to efficiency of neutralization.

What do magnesium salts cause?

What do aluminum salts cause?

Why are they commonly give together?

Any impact on the kidneys?

A
  1. Magnesium salts can cause osmotic diarrhea.
  2. Aluminum salts can cause constipation.
  3. Commonly administered in combination to minimize impact on bowel function.
  4. Both Mg2+ and Al3+ absorbed and excreted by the kidneys, should not be taken long term in renal insufficiency.
40
Q

antacids may bind/affect absorption of other drugs or increase intragastric pH so drug dissolution or solubility is altered. Do not give within 2 hours of administration of what other three drugs?

A
  • Tetracyclines
  • fluoroquinolones
  • Iron
41
Q

Which are more effective in treating peptic ulcers, H2RAs or PPIs?

A

PPIs

42
Q

In which category of drugs discussed here do we see the development of tolerance?

A

H2RAs

43
Q

Why no tolerance development in PPIs?

A

Probably because site of action is distal to the action of histamine.

44
Q

What can happen when PPIs and H2RAs are discontinued?

A
  1. Rebound dyspeptic symptoms and acid hypersecretion have been reported following discontinuation of PPIs and H2RAs.
45
Q

Bismuth compounds include bismuth subsalicylate and bismuth subcitrate potassium. What is their MOA?

How about the subsalicylate specifically?

A
  1. precise mechanism unknown; bismuth coats ulcers and erosions creating a protective layer against acid and pepsin. Also stimulates prostaglandin, mucus, and bicarbonate secretion.
    1. Salicylate (like ASA) readily absorbed; inhibits intestinal prostaglandin and chloride secretion (reduces stool frequency and liquidity in infectious diarrhea).
    2. Bismuth has direct antimicrobial activity against H. pylori.
46
Q

What is bismuth subcitrate potassium available as?

A

Only available in prescription combination with metronidazole and tetracycline for H. pylori

47
Q

What are three therapeutic uses of Bismuth compounds?

A
  1. Dyspepsia and acute diarrhea – widely used OTC (even with lack of comparative trials).
  2. Traveler’s diarrhea.
  3. H. pylori infection – part of 4 drug combination regimen.
48
Q

What is the prostaglandin analogue we need to know?

A

misoprostol

49
Q

What is the MOA of misoprostol?

A

methyl analog of PGE1, mucosal protective and acid inhibitory. May stimulate mucus and bicarbonate secretion and enhance mucosal blood flow. Binds prostaglandin receptors on parietal cells reducing histamine stimulated cAMP production causing modest acid inhibition.

50
Q

What is the therapeutic use of misoprotol?

A
  1. Prevention of NSAID induced ulcers – decreases incidence but is not widely used due to adverse effect profile and need for multiple daily dosing (PPIs may be as effective and are better tolerated).
51
Q

What are the ADR’s of misoprostal?

A
  1. 10-20% experience diarrhea and cramping abdominal pain. Not well tolerated.
  2. Stimulates uterine contractions; thus, contraindicated in pregnancy or in those of child-bearing years without a negative pregnancy test.
52
Q

Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide, and is used for stress-related mucosal injury. It is administered as a slurry through an NG tube.

What is the MOA of this drug?

A
  1. precise mechanism unknown; negatively charged sucrose sulfate binds positively charged proteins at base of erosions forming a physical barrier that restricts further damage; also stimulates mucosal prostaglandin and bicarbonate secretion.
53
Q

What are the ADRs of sucralfate?

A

not absorbed = virtually no systemic side effects (avoid prolonged use in renal failure/ insufficiency due to small amount aluminum absorption). 2% experience constipation (due to aluminum salt).

54
Q

When should you test for H. pylori?

A
  1. Active PUD (regardless of NSAID use status, those with active PUD should be tested and treated for H. pylori if infection found).
  2. Past history of documented peptic ulcer (without treatment for H. pylori).
  3. Gastric mucosa associated lymphoid tissue (MALT) lymphoma.
  4. “Test-and-treat” strategy for patients with uninvestigated dyspepsia, < 55 years old, and have no alarm features (bleeding, anemia, early satiety, unexplained weight loss, progressive dysphagia).
55
Q

What are the most effective drug regimens to heal ulcers and kill H. pylori?

A
  1. most effective regimens are combinations of two or three antibiotics + PPI.

GI-II, Exam 1 (8 decks)

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