Transcript Histamine and Antihistamines

Gastric Acid Modifiers
or
Gastric Acid Suppression (GAS)
November 27, 2007
Frank F. Vincenzi
$13 billion market in 1998, inc. at 3%/yr
Drug list for gastric acid modifiers
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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®)
Trivial mechanisms of
gastric acid modification
• Acid neutralization and/or physical protection
– Sucralfate (Carafate®)
( duodenal>gastric>>>GERD)
(may decrease bioavailability of other drugs)
– Aluminum hydroxide + magnesium hydroxide
(Gelusil®, Maalox®, Mylanta®)
– Bismuth subsalicylate (Pepto-Bismol®) & other
bismuth compounds
– Calcium carbonate (Tums®)
Gastric acid secretion
Factors affecting gastric acid secretion
MC = mast cell like cell
or enterochromaffin like cell
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)
H2 antihistamine prototypes:
decreased gastric acid secretion
• cimetidine (Tagamet®)
binds the androgen receptor
inhibits CYP
(2C19 ; 1A2, 2D6)
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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)
Histaminergic (H2) and muscarinic stimulation of
gastric acid secretion in isolated parietal cells:
antagonism by cimetidine and atropine, respectively
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)
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)
H2 antihistamines: adverse reactions
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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
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)
Factors affecting gastric acid secretion
MC = mast cell like cell
or enterochromaffin like cell
Omeprazole:
irreversible
inhibition of
the proton
pump enzyme
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?
Omeprazole (Prilosec®): Indications
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Active duodenal ulcer
Helicobacter eradication (with combotherapy)
Severe erosive esophagitis
Symptomatic poorly responsive gastroesophageal
reflux disease (GERD)
• Pathological hypersecretory conditions (ZollingerEllison syndrome
Omeprazole & esomeprazole compared clinically in
patients with Gastroesophageal Reflux Disease (GERD)
100
90
80
70
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40
30
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10
0
esomeprazole
% of day at pH >4
omeprazole
Adapted from Baker, 2001
Clinical Trials of Medical Treatment of
Gastroesophageal Reflux Disease (GERD)
Kahrilas, 1999
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
Some concerns about long term GAS
• Malabsorption of nutrients?
• Increased susceptibility to enteric infection?
• Development of GI neoplasia (from inc
gastrin)?
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."
Gastric acid suppression (GAS) by H2
receptor antagonists (H2RAs) or proton pump
inhibitors (PPIs): association with pneumonia
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> 360,000 pts., 5551 first pneumonia
>10K H2RAs, >12K 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 communityacquired pneumonia.
Laheji et al., JAMA 292: 1955-1960, 2004
Adverse Reaction Concerns
Gulmez et al., Arch Intern Med. 2007;167:950-955.
Use of PPIs within the past 7 days was associated with a
fivefold higher risk of community acquired pneumonia and
use of > 12 weeks was associated with increased risk of
CAP (OR 1.3).
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 PopulationBased, Case-Control Study
Gastroenterology. 2007;133:755-760
Long-term proton pump inhibitor therapy at a
regular dose is not associated with a significantly
increased risk of colorectal cancer.