Post on 29-Mar-2015
Agents to Treat Gastric Acidity and Gastroesophageal
Reflux Disease(GERD)
Presented byAbby 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• Acid Indigestion
• Regurgitation• 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
H203 NH3 + CO2
Urea
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
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
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
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 H2-receptors
• 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
Ranitidine HCl (Zantac)
Famotidine (Pepcid)
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.