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 H20H20 3 NH 3 + CO 2 Urea
H. pylori Secret proteins and toxins that interact with the stomachs 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 – Barretts Esophagus – Precursor to Esophageal Cancer
Causes of GERD Abnormalities with the Lower Esophageal Sphincter, or LES Stomach Abnormalities – Hiatal hernia – Link Link
Release of Gastric acid Histamine stimulates acid release by interacting with the histamine receptor, H 2 Acetylcholine activates the cholinergic receptors Gastrin is released when food is present in the stomach
Treatments Antacids Alginates Sucralfate Proton Pump Inhibitors Histamine H 2 -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 AlCl 3 + 3 H 2 O
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
Treatments Histamine H 2 -recptor antagonists (H 2 RAs) The hormone, histamine stimulates the release of acid by interacting with the histamine receptor, or H 2 receptor. Inhibit acid secretion by competitively and reversibly blocking parietal cell H 2 - receptors Less potent then PPIs
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
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
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 H 2 RAs (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 PPIs 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.