Agents to Treat Gastric
Acidity and Gastroesophageal
Reflux Disease
(GERD)
Presented by
Abby Roth
Overview
• Introduction
– Symptoms
• Causes
– Peptic Ulcer Disease
• H. pylori
• NSAIDs
– GERD
• Treatments
Who is Affected?
Gastric acidity and GERD affects
people of all ages, races, and gender
Symptoms
• Heartburn
• Regurgitation
• Acid Indigestion • Nausea
Symptoms Continued
• Hoarseness
• Sore Throat
• Chest Pain
• Bad Breath
• Dry Cough
• Asthma*
Symptoms in Children
• Vomiting
• Coughing
• Breathing
Problems
Acid-Peptic Disorders
• Peptic Ulcer Disease
–Occurs when there
is an imbalance
between the
mucosal defense
factors and the
acid and pepsin.
Helicobacter pylori Infection
• Causes 80% of peptic ulcers
• Survives the acid environment by attaching to
the sugar molecules that line the stomach wall
• Uses the mucus
layer as protection
H. pylori
• Produce large amounts of
urease
Urease
H20
Urea
3 NH3 + CO2
H. pylori
• Secret proteins and toxins that interact
with the stomach’s epithelial cells
• Leads to inflammation and damage
NSAIDs
• Aspirin, Ibuprofen,
Naproxen
• Can have an affect at very
low doses
• Suppresses
cylooxygenase-1
• Decrease production of
prostaglandins
What is GERD?
• Condition where the stomach
acid/content is pushed back or
“refluxed” into the esophagus
• Affects 10 million Americans
• Approximately 7% have daily
symptoms
• Link
GERD vs. NERD
• Patients suffering symptoms are placed
in two groups
–Non-erosive reflux disease, or NERD
–Erosive esophagitis
• Erosive esophagitis is characterized by
swelling and Inflammation
–Barrett’s Esophagus
–Precursor to Esophageal Cancer
Causes of GERD
• Abnormalities with the
Lower Esophageal
Sphincter, or LES
• Stomach Abnormalities
–Hiatal hernia
–Link
Causes
• Medications
–NSAIDs
–Calcium Channel Blockers (high
blood pressure, angina)
Medications
–Anticholinergics (urinary tract
disorders)
–Beta Adrenergic Agonists (asthma)
–Dopamine (Parkinson’s disease)
Causes
• Food and Drinks
– Carbonated beverages
– Chocolate 
– Alcohol
– Citrus Fruits
– Coffee or Tea
– Fatty foods
– Containing tomatoes
– Mint
– Spicy Food
Causes
• Smoking
– Damages mucus
membranes
– Impairs muscle
reflexes in the throat
– Increases acid
secretion
– Reduces LES function
and salivation
Causes
• Obesity
• Laying down after
a large meal
• Eating close to
bed time
• Exercise
Release of Gastric Acid
Release of Gastric acid
• Histamine stimulates
acid release by
interacting with the
histamine receptor, H2
• Acetylcholine activates
the cholinergic
receptors
• Gastrin is released
when food is present in
the stomach
Treatments
•
•
•
•
•
•
•
Antacids
Alginates
Sucralfate
Proton Pump Inhibitors
Histamine H2-Recptor Antagonists
Prokinetics
New Treatments
Antacids
• Quick but short term
• Buffer gastric acid, increasing the pH
• Neutralize acid by the following
reaction
Al(OH)3 + 3 HCl
AlCl3 + 3 H2O
Antacids
–Maalox
• Al(OH)3 (aluminum
hydroxide), Mg(OH)2
(magnesium hydroxide)
Antacids
• Tums
• CaCO3 (calcium
carbonate)
Antacids
–Pepto-Bismol
• C7H5BiO4 (bismuth
subsalicylate)
Antacids
–Alka-Seltzer
• NaHCO3 (sodium
bicarbonate)
Alginates
• Alginates
–Usually combined with an antacid
–Forms protective barrier on top of
gastric contents
–Gaviscon
• Sodium Alginate, Sodium
Bicarbonate, and Calcium Carbonate
–Link
Alginates
• Polysaccharide
found in the cell
walls of brown
algae
• Sodium alginate is
the sodium salt of
alginic acid
Alginic Acid
Sucralfate
• Reacts with stomach acid to from a cross
linked viscous polymer that acts as an acid
buffer
• Can bind to proteins on the surface of an ulcer
to prevent further acid damage
• Has been shown to aid in healing by
promoting epidermal growth factors and
prostaglandins
Sucralfate (Carafate)
Proton Pump Inhibitors
• Proton pump inhibitors (PPIs)
– Inhibits the gastric acid pump,
H+/K+ ATPase
– Are prodrugs
PPIs
• Diffuse into the parietal cells of the stomach
and accumulates
• Activated by proton-catalyzed formation of
sulfenic acid
• This prevents the drug from diffusing out
• Activated form then irreversibly binds at the
sulfhydryl groups of the cysteins of the H+/K+
ATPase
• Link
Cysteine
PPIs
Rabeprazol (Acipex)
PPIs
Lansoprazole (Prevacid)
PPIs
Esomeprazole (Nexium)
PPIs
Omeprazole (Prilosec)
Omeprazole/sodium bicarbonate (Zegerid)
PPIs
Pantoprazole (Protonix)
Treatments
• Histamine H2-recptor antagonists (H2RAs)
• The hormone, histamine stimulates the
release of acid by interacting with the
histamine receptor, or H2 receptor.
• Inhibit acid secretion by competitively
and reversibly blocking parietal cell H2receptors
• Less potent then PPI’s
Agonist vs. Antagonist
• An agonist is a drug that
produces the same
response at a receptor as
the natural messenger
• An antagonist is a drug
which binds to a receptor
without activating it,
prevent an agonist or
natural messenger from
binding
Histamine
H2RAs
Cimetidine (Tagamet)
H2RAs
Nizatidine (Axid)
Other H2RAs
Famotidine (Pepcid)
Ranitidine HCl (Zantac)
Treatments
• Prokinetics
–Increase LES function
–Release stomach contents by
•Activating serotonin receptors
•Acting on dopaminergic
receptors
Prokinetics
Metoclopramide (Reglan, Degan)
Prokinetics
Domperidone (Motilium, Costi)
Prokinetics
Cisapride (Prepulsid, Propulsid)
Prokinetics
• Rarely used because of severe side
effects
– Fatigue
–Tremors
–Parkinsonism
–Tardive Dyskinesia
–Severe cardiac events
New Treatments
• Cholecystokinin2 receptor
antagonists (CCK2)
• Potassium competitive acid
blockers (P-CABs)
Treatments
• Cholecystokinin2 receptor
antagonists (CCK2)
–Block the CCK2 receptors inhibiting
acid secretion
–Still in clinical trials
–Best use in combination with PPI’s
CCK2
Itriglumide
CCK2
Z-360
Treatments
• Potassium competitive acid blockers (P-CABs)
– Target H+/K+ ATPase
– Ionically binds to the proton pump
– Specific for the K+ binding region and
prevents acid secretion
– Binds reversibly
– Still in clinical trials
P-CABs
Revaprazan
P-CABs
Soraprazan
Treatment for H. pylori
• Amoxicillin + clarithromycin
+ proton pump inhibitor
• Metronidazole +
clarithromycin + proton
pump inhibitor
• Bismuth subsalicylate +
metronidazole +
tetracycline + proton pump
inhibitor
Assigned Reading
• Vesper, J.B. et all, Gastroesophageal Reflux
Diesease, Is there More to the Story?,
ChemMedChem (2008), 3, 552-559.
Homework Questions
• What is an antagonist and how do the H2RAs
(histamine receptor antagonists) act as one?
• Explain the precise biological mechanism
whereby prokinetics achieve their effect,
including the receptors they act upon. Are they
agonists or antagonists? Of which chemical
messenger?
• What is a prodrug? What causes the PPI’s to
become an active drug?
• Bacteria in the upper GI tract may play a role in
GERD. Explain.
References
• Bak, Young-Tae. Management Strategies for Gastroesophageal
Reflux Disease. Journal of Gastroenterology and Hepatology
(2004), 19, S49-S53.
• Horn, J. Understanding the Pharmacodynamic and Pharmacokinetic
Differences between proton pump inhibitors- focus on pKa and
metabolism. AP&T (2006), 2, 340-350.
• Pettit, M. Treatment of Gastroesophageal Reflux Disease. Pharm
World Sci (2005) 27, 432-435.
• Vakil, N., New Pharmacological Agents for the Treatment of
Gastroesophageal Reflux Disease. AP&T (2006), 19, 1041-1049.
• Vesper, J.B. et all, Gastroesophageal Reflux Diesease, Is there More
to the Story?, ChemMedChem (2008), 3, 552-559.
• Goodman and Gilman pg 967-980.
• Patrick pg 643-671.