agents to treat gastric acidity and gastroesophageal reflux disease (gerd) presented by abby roth
TRANSCRIPT
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Agents to Treat Gastric Acidity and Gastroesophageal
Reflux Disease(GERD)
Presented byAbby Roth
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Overview• Introduction– Symptoms
• Causes–Peptic Ulcer Disease• H. pylori• NSAIDs
–GERD• Treatments
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Who is Affected?
Gastric acidity and GERD affects people of all ages, races, and gender
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Symptoms
• Heartburn• Acid Indigestion
• Regurgitation• Nausea
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Symptoms Continued
• Hoarseness• Sore Throat• Chest Pain• Bad Breath• Dry Cough• Asthma*
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Symptoms in Children
• Vomiting • Coughing• Breathing
Problems
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Acid-Peptic Disorders• Peptic Ulcer Disease–Occurs when there
is an imbalance between the mucosal defense factors and the acid and pepsin.
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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
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H. pylori• Produce large amounts of
urease Urease
H203 NH3 + CO2
Urea
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H. pylori• Secret proteins and toxins that interact
with the stomach’s epithelial cells• Leads to inflammation and damage
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NSAIDs• Aspirin, Ibuprofen,
Naproxen• Can have an affect at very
low doses• Suppresses cylooxygenase-1 • Decrease production of
prostaglandins
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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
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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
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Causes of GERD• Abnormalities with the
Lower Esophageal Sphincter, or LES
• Stomach Abnormalities–Hiatal hernia–Link
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Causes
• Medications–NSAIDs–Calcium Channel Blockers (high
blood pressure, angina)
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Medications–Anticholinergics (urinary tract
disorders)–Beta Adrenergic Agonists (asthma)–Dopamine (Parkinson’s disease)
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Causes• Food and Drinks– Carbonated beverages– Chocolate – Alcohol– Citrus Fruits– Coffee or Tea– Fatty foods– Containing tomatoes– Mint– Spicy Food
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Causes• Smoking–Damages mucus
membranes– Impairs muscle reflexes
in the throat– Increases acid secretion–Reduces LES function
and salivation
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Causes• Obesity• Laying down after
a large meal• Eating close to
bed time• Exercise
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Release of Gastric Acid
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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
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Treatments• Antacids• Alginates• Sucralfate• Proton Pump Inhibitors• Histamine H2-Recptor Antagonists
• Prokinetics• New Treatments
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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
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Antacids–Maalox •Al(OH)3 (aluminum
hydroxide), Mg(OH)2 (magnesium hydroxide)
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Antacids• Tums
•CaCO3 (calcium carbonate)
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Antacids–Pepto-Bismol•C7H5BiO4 (bismuth subsalicylate)
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Antacids–Alka-Seltzer•NaHCO3 (sodium bicarbonate)
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Alginates• Alginates–Usually combined with an antacid–Forms protective barrier on top of
gastric contents–Gaviscon• Sodium Alginate, Sodium
Bicarbonate, and Calcium Carbonate–Link
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Alginates• Polysaccharide
found in the cell walls of brown algae• Sodium alginate is
the sodium salt of alginic acid
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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
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Proton Pump Inhibitors• Proton pump inhibitors (PPIs)– Inhibits the gastric acid pump,
H+/K+ ATPase– Are prodrugs
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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
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Cysteine
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PPIs
Rabeprazol (Acipex)
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PPIs
Esomeprazole (Nexium)
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PPIs
Omeprazole (Prilosec)Omeprazole/sodium bicarbonate (Zegerid)
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PPIs
Pantoprazole (Protonix)
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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
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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
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Histamine
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H2RAs
Cimetidine (Tagamet)
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H2RAs
Nizatidine (Axid)
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Other H2RAs
Ranitidine HCl (Zantac)
Famotidine (Pepcid)
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Treatments• Prokinetics–Increase LES function –Release stomach contents by •Activating serotonin receptors•Acting on dopaminergic receptors
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Prokinetics
Metoclopramide (Reglan, Degan)
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Prokinetics
Domperidone (Motilium, Costi)
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Prokinetics
Cisapride (Prepulsid, Propulsid)
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Prokinetics• Rarely used because of severe side
effects– Fatigue–Tremors–Parkinsonism–Tardive Dyskinesia–Severe cardiac events
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New Treatments
•Cholecystokinin2 receptor antagonists (CCK2)
•Potassium competitive acid blockers (P-CABs)
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Treatments• Cholecystokinin2 receptor
antagonists (CCK2)
–Block the CCK2 receptors inhibiting acid secretion–Still in clinical trials–Best use in combination with PPI’s
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CCK2
Itriglumide
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CCK2
Z-360
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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
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P-CABs
Revaprazan
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P-CABs
Soraprazan
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Treatment for H. pylori
• Amoxicillin + clarithromycin + proton pump inhibitor
• Metronidazole + clarithromycin + proton pump inhibitor
• Bismuth subsalicylate + metronidazole + tetracycline + proton pump inhibitor
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Assigned Reading
• Vesper, J.B. et all, Gastroesophageal Reflux Diesease, Is there More to the Story?, ChemMedChem (2008), 3, 552-559.
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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.
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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.