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

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 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.