Gastric Acid Modifiers or Gastric Acid Suppression GAS

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Gastric Acid ModifiersorGastric Acid
Suppression (GAS)

• November 27, 2007
• Frank F. Vincenzi

13 billion market in 1998, inc. at 3/yr
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Drug list for gastric acid modifiers

• cimetidine (Tagamet generic, OTC)
• famotidine (Pepcid generic, OTC)
• lansoprazole (Prevacid, )
• misoprostol (Cytotec)
• nizatidine (Axid)
• omeprazole (Prilosec)
• pirenzepine (not avail in U.S.)
• ranitidine (Zantac)
• sucralfate (Carafate)

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Trivial mechanisms ofgastric acid modification

• Acid neutralization and/or physical protection
• Sucralfate (Carafate)( duodenalgtgastricgtgtgtGERD)
  (may decrease bioavailability of other drugs)
• Aluminum hydroxide magnesium hydroxide
  (Gelusil, Maalox, Mylanta)
• Bismuth subsalicylate (Pepto-Bismol) other
  bismuth compounds
• Calcium carbonate (Tums)

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Gastric acid secretion
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Factors affecting gastric acid secretion
MC mast cell like cellor enterochromaffin like
cell
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Histamine receptors

• H1 - smooth muscle, exocrine glands, vascular
  endothelium, brain coupled to phospholipase C,
  leading to IP3 and diacylglycerol (DAG)
• H2 - parietal cells, heart, vascular smooth
  muscle, mast cells, brain coupled to cAMP
  production
• H3 - presynaptic, brain, myenteric plexus (no
  therapeutic applications, yet)

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H2 antihistamine prototypesdecreased gastric
acid secretion

• cimetidine (Tagamet) binds the androgen
  receptor inhibits CYP (2C19 1A2, 2D6)
• well absorbed, poor CNS penetration half life
  2 hours (800 mg HS, 300 mg QID, 400 mg AM HS)
• ranitidine (Zantac half life 2.5 hours (150
  mg BID, 300 mg HS)
• famotidine (Pepcid)
• nizatidine (Axid) (better bioavailability)

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Histaminergic (H2) and muscarinic stimulation of
gastric acid secretion in isolated parietal
cells antagonism by cimetidine and atropine,
respectively
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Indication for H2 antihistamines chronic
recurrent ulcers

• Ulcers induced by drugs (NSAIDs)
• (may use sucralfate and/or misoprostol)
• Ulcers associated with hypersecretion (Zollinger-
  Ellison syndrome)
• Ulcers associated with malignancy
• Helicobacter pylori-positive ulcers (with
  inflammation of stomach duodenum - most
  common type of ulcer)

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Indication for H2 antihistamines chronic
recurrent ulcers

• Ulcers induced by drugs (NSAIDs)
• Ulcers associated with hypersecretion (Zollinger-
  Ellison syndrome)
• Ulcers associated with malignancy
• Helicobacter pylori-positive ulcers (with
  inflammation of stomach duodenum - most
  common type of ulcer)

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H2 antihistamines adverse reactions

• Headache
• Dizziness
• Diarrhea, constipation
• Skin rashes
• For cimetidine loss of libido, gynecomastia,
  impotence
• drug interactions based on inhibition of
  CYP1A2, CYP2C19 and CYP2D6, less with ranitidine,
  no inhibition with famotidine or nizatidine

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A new way to decrease acid secretion proton pump
inhibitors (PPIs)

• omeprazole (Prilosec) recently esomeprzole
  (Nexium)
• lansoprazole (Prevacid)
• Inhibit the H/K pump of the parietal cell plasma
  membrane - probably from the outside - somewhat
  like digitalis inhibition of Na/K pump - but
  irreversibly
• Adverse reactions headache, nausea,
  diarrhea(and, rarely, Stevens-Johnson syndrome)

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Factors affecting gastric acid secretion
MC mast cell like cellor enterochromaffin like
cell
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Omeprazole irreversible inhibition of the proton
pump enzyme
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Proton Pump Inhibitors (PPIs) Common Features

• Enteric coating prevents premature destruction
• Metabolized extensively by liver (2C19 3A4) -
  avoid hepatic disease
• Typically a short plasma half-life, but a long
  duration of action - covalent inactivation of the
  proton pump
• Absorbed and then ion-trapped and activated in
  acidic stomach.
• Best taken with or before meals (acid labile)
• Daily dosing may result in 70 of proton pumps
  inactivated in 2-5 days
• Hypergastrinemia in 5-10 of patients - tumors?

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Omeprazole (Prilosec) Indications

• Active duodenal ulcer
• Helicobacter eradication (with combotherapy)
• Severe erosive esophagitis
• Symptomatic poorly responsive gastroesophageal
  reflux disease (GERD)
• Pathological hypersecretory conditions
  (Zollinger-Ellison syndrome

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Omeprazole esomeprazole compared clinically in
patients with Gastroesophageal Reflux Disease
(GERD)
Adapted from Baker, 2001
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Clinical Trials of Medical Treatment of
Gastroesophageal Reflux Disease (GERD)
Kahrilas, 1999
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Treating GERD
I Sporadic - lifestyle, weight, antacids or H2
block PRN II Frequent (2-3 x/wk) - PPIs, better
than H2 blockers III Chronic unrelenting - PPIs
1-2 x/day
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Some concerns about long term GAS

• Malabsorption of nutrients?
• Increased susceptibility to enteric infection?
• Development of GI neoplasia (from inc gastrin)?

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Adverse Reaction Concerns
Malaz Boustani, et al., Journal of the American
Geriatrics Society, August, 2007 A 5-year
observational study included 1,558 cognitively
normal African-Americans aged 65 and older. After
controlling for other possible factors, nearly
18 of H2A users studied exhibited signs of
cognitive impairment. "Taking these medications
continuously appears to put older
African-Americans at greater risk for the
development of cognitive impairment," said "We
need to study this further to determine how acid
blockers might be causing or creating this effect
and if it occurs only in African-Americans."
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Gastric acid suppression (GAS) by H2 receptor
antagonists (H2RAs) or proton pump inhibitors
(PPIs) association with pneumonia

• gt 360,000 pts., 5551 first pneumonia
• gt10K H2RAs, gt12K PPIs (some both)
• 4.5 x (3.8-5.1) more often on GAS than not
• 1 case per 226 PPI pts (NNH)
• RR of first pneumonia 1.89 (1.36-2.62) for H2
  blkrs, and 1.63 (1.07-2.48) for PPIs
• Use of gastric acid-suppressive therapy was
  associated with an increased risk of
  community-acquired pneumonia.

Laheji et al., JAMA 292 1955-1960, 2004
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Adverse Reaction Concerns
Gulmez et al., Arch Intern Med.
2007167950-955. Use of PPIs within the past 7
days was associated with a fivefold higher risk
of community acquired pneumonia and use of gt 12
weeks was associated with increased risk of CAP
(OR 1.3).
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Adverse Reaction Concerns
Robertson DJ, Larsson H, Friis S, Pedersen L
Baron JA Sorensen HT, Proton Pump Inhibitor Use
and Risk of Colorectal Cancer A
Population-Based, Case-Control Study Gastroenterol
ogy. 2007133755-760 Long-term proton pump
inhibitor therapy at a regular dose is not
associated with a significantly increased risk of
colorectal cancer.