Drugs to Treat Gastric Acidity, Peptic Ulcer Disease, and Gastroesophageal Reflux Disease

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Drugs to Treat Gastric Acidity, Peptic Ulcer
Disease, and Gastroesophageal Reflux Disease
Michael A. Pezzone, M.D., Ph.D. Assistant
Professor of Medicine and Pharmacology
University of Pittsburgh, Pittsburgh,
Pennsylvania USA Division of Gastroenterology,
Hepatology and Nutrition and Department of
Pharmacology
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Learning Objectives

• Know the major classes of acid-suppressive drugs
  and their mechanisms of action
• Know the common side effects of acid-suppressive
  drugs
• Know the specific treatment of acid-peptic
  disorders

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Background Gastroesophageal Reflux Disease (GERD)

• A syndrome of symptomatic reflux of gastric
  contents into the esophagus (i.e. heartburn)
• Erosive
• Non-erosive (NERD)
• Gastric reflux contains a variety of esophageal
  irritants
• Acid (2-3 liters per day)
• Pepsin
• Bile

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GERD Prevalence and Impact on QOL

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GERD Treatment Options
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Classes of Agents

• Proton Pump Inhibitors
• Histamine H2-Receptor Antagonists
• Prostaglandin Analogs
• Cytoprotectants
• Antacids

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1. Proton Pump Inhibitors (PPIs)

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PPIs

• Most potent suppressors of acid secretion
• Diminish basal and stimulated acid production by
  80-95
• 24-48 hr effects on acid suppression
• Acid-activated pro-drugs

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PPIs

• Irreversibly inhibit H/KATPase function to
• Block gastric acid secretion
• Decrease pepsin concentration
• Increase gastric pH
• Secretion of acid only resumes when new proton
  pumps are deployed
• Steady-state inhibition (affecting 70 of pumps)
  may take 2-5 days

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PPI Pharmacology

• Pro-drugs with pKa of approximately 4
• Activated only when pH decreases below 4
• Occurs only in parietal cell secretory canaliculi
• Achieved only when parietal cell activation
  occurs (after meals)
• Most effective after a prolonged fast when large
  amounts of active proton pumps are present (i.e.
  breakfast)
• Unstable at low pH (enteric coated or gelatin
  shell)

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Available PPIs

• Esomeprazole (Nexium)
• Lansoprazole (Prevacid) (iv)
• Omeprazole (Prilosec, generic, OTC)
• Pantoprazole (Protonix) (iv)
• Rabeprazole (Aciphex)
• All have equivalent efficacy at comparable
  doses

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PPI Structures(substituted benzimidazoles)

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Activation of Substituted Benzimidazoles

H/KATPase
forms a disulfide bond with the cystine
residues within the alpha subunit of the enzyme
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PPI Metabolism

• Rapidly absorbed
• Highly protein bound
• Extensively metabolized in the liver by the P450
  system (CYP2C19 and CYP3A4)
• Sulfated metabolites are excreted in the urine or
  feces
• Hepatic disease reduces the clearance of
  lansoprazole--reduce dose

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Metabolized by hepatic CYPs
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Common PPI Side Effects

• Headache (2.9-6.9) vs. Placebo (2.5-6.3)
• Diarrhea (3) vs. Placebo (3.1)
• Abdominal pain (2.4-5.2) vs. Placebo
  (3.1-3.3)
• Constipation (1.1-1.5) vs. Placebo (0-0.8)
• B12 malabsorption reported with omeprazole

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Drug-Drug Interactions

• Warfarin
• Esomeprazole
• Lansoprazole
• Omeprazole
• Rabeprazole
• Diazepam
• Esomeprazole
• Omeprazole

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2. Histamine H2-Receptor Antagonists (H2RAs)

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H2RAs

• Reversibly compete with histamine for binding to
  H2 receptors on the basolateral membrane of
  parietal cells
• Less potent than PPIs but still suppress acid by
  70 over 24 hrs
• Predominantly inhibit basal acid suppression
  (nocturnal)
• Available OTC

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Available H2RAs

• Cimetidine (Tagamet)
• Ranitidine (Zantac)
• Famotidine (Pepcid) (iv)
• Nizatidine (Axid)

All exist in generic form
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Pharmacokinetics

• Rapidly absorbed after oral administration
• Serum concentrations peak in 1-3 hr
• Therapeutic levels maintained up to 12 hrs
• Small percentage is protein bound
• 10 to 35 metabolized by the liver
• Drugs and metabolites primarily excreted by
  kidneys (reduce doses in renal disease)
• Development of tolerance (3 days)
• Rebound response upon discontinuation

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Common H2RA Side Effects

• All less than 3
• Diarrhea
• Headache
• Drowsiness
• Fatigue
• Muscular pain
• Constipation
• Much less common
• Confusion, delirium in the elderly
• Associated with thrombocytopenia
• Cimetidine anti-androgen effects

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Drug-Drug Interactions

• Avoided by not using cimetidine
• Cimetidine inhibits CYPs

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3. Prostaglandin Analogs Misoprostol

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Protective Effects of Prostaglandins

• PGE2 and PGI2 synthesized by gastric mucosa
• Acid-reducing effects
• Bind to EP3 receptors on parietal cells
• Decrease acid production
• Cytoprotective effects
• Stimulation of mucin and bicarbonate
• Increase mucosal blood flow
• Contrast with NSAIDS which diminish prostaglandin
  formation by inhibition of cycloxygenase and lead
  to ulcer formation

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Misoprostol Cytotec

• Synthetic analog of PGE1
• Enhanced potency
• Increased oral bioavailability
• Inhibit basal acid secretion (85-95)
• Inhibit stimulated acid secretion (75-85)

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Misoprostol Structure

PGE1
Misoprostol
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Pharmacokinetics

• Rapidly absorbed
• Rapidly de-esterfied to misoprostol acid--the
  active metabolite
• Therapeutic effect peaks at 60-90 minutes
• Lasts 3 hours (qid dose required)
• Free acid excreted mainly in urine

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Side Effects

• Diarrhea abdominal cramps as high as 30
• Begins within 2 weeks and often resolves
  spontaneously in 1 week
• Can exacerbate inflammatory bowel disease
• Contraindicated during pregnancy

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4. Sucralfate Carafate

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Sucralfate

• Sulfated polysaccharide
• Acid activated
• Administered on an empty stomach 1 hr before
  meals
• Undergoes cross-linking to produce a thick,
  viscous polymer that adheres to epithelial cells
  and ulcer craters for up to 6 hrs
• Stimulates local prostaglandin synthesis
• Binds bile acids

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Sucralfate

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Common Side Effects

• Constipation (2)
• Aluminum toxicity
• Avoid in renal failure
• May impair absorption of other drugs

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5. Antacids

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Antacids

• Sodium bicarbonate
• CaCO3
• Mg2 hydroxides
• Al3 hydroxide

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Antacids

• Given orally 1-3 hrs after meals and bedtime
• Single dose provides 120mEq neutralizing
  capacity--equivalent to one dose of an H2RA
• Mg2 based preparations increase motility
• Diarrhea
• Al3 based preparations relax smooth muscle
• Constipation
• Ca2 based preparations release CO2
• Belching, nausea, distension, and flatulence.

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Common Side Effects

• Aluminum toxicity with renal disease
• Osteoporosis, enchephalopathy, myopathy
• Hypercalcemia
• Phosphate retention
• Calcium precipitation in the kidney
• Impair absorption of some drugs
• Take 2 hrs before or after other drugs

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Treatment of GERD

• Goals
• Resolution of symptoms (NERD)
• Healing of esophagitis
• Healing rates
• Drug 4wks 8wks
• PPIs 80 90
• H2RAs 50 75

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GERD Therapy (uncomplicated)

• Empiric treatment with PPI or H2RA
• Consider step-up therapy
• EGD
• Onset older than 40 yoa
• Symptoms greater than 10 years
• Not better with a PPI
• Alarm symptoms such as dysphagia, weight loss,
  melena
• When stable, step-down therapy

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Peptic Ulcer Disease (PUD)

• Imbalance between mucosal defense factors and
  aggravating factors (acid and pepsin)
• Worldwide prevalence 10
• 80-90 of ulcers related to H. pylori infection
  or chronic NSAID use
• Impaired production of somatostatin by D cells
• Reduction of cytoprotective prostaglandins (PGE2
  and PGI2)

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Healing Rates of PUD

• PPIs 80-90
• H2RAs, Misoprostol 60-75
• Invtravenous PPI is clearly the preferred therapy
  in patients with acute bleeding uclers

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H. Pylori Treatment Reduces PUD Recurrence

• 10-20 vs. 55-70 (untreated)
• Triple Therapy
• PPI BID
• Clarithromycin BID
• Amoxicillin or Metronidazole

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NSAID Ulcer Prophylaxis

• Chronic NSAID users have a 2-4 risk of
  developing symptomatic PUD
• PPIs are more superior to H2RAs and misoprostol
  in preventing PUD recurrence
• Gastric ulcers 5-13 vs. 10-16
• Duodenal ulcers 0.5-3 vs. 4-10