1、Agents to Treat Gastric Acidity and Gastroesophageal Reflux Disease(GERD)1Overview IntroductionSymptoms CausesPeptic Ulcer Disease H.pylori NSAIDsGERD Treatments2Who is Affected?Gastric acidity and GERD affects people of all ages,races,and gender 3Symptoms Heartburn Acid Indigestion Regurgitation Na
2、usea 4Symptoms Continued Hoarseness Sore Throat Chest Pain Bad Breath Dry Cough Asthma*5Symptoms in Children Vomiting Coughing Breathing Problems6Acid-Peptic Disorders Peptic Ulcer DiseaseOccurs when there is an imbalance between the mucosal defense factors and the acid and pepsin.7Helicobacter pylo
3、ri 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 protection8H.pylori Produce large amounts of urease UreaseH203 NH3+CO2Urea9H.pylori Secret proteins and toxins that interact with the stomachs
4、epithelial cells Leads to inflammation and damage10NSAIDs Aspirin,Ibuprofen,Naproxen Can have an affect at very low doses Suppresses cylooxygenase-1 Decrease production of prostaglandins 11What is GERD?Condition where the stomach acid/content is pushed back or“refluxed”into the esophagus Affects 10
5、million Americans Approximately 7%have daily symptoms Link12GERD vs.NERD Patients suffering symptoms are placed in two groups Non-erosive reflux disease,or NERDErosive esophagitis Erosive esophagitis is characterized by swelling and InflammationBarretts EsophagusPrecursor to Esophageal Cancer13Cause
6、s of GERD Abnormalities with the Lower Esophageal Sphincter,or LES Stomach AbnormalitiesHiatal herniaLink14Causes MedicationsNSAIDsCalcium Channel Blockers(high blood pressure,angina)15MedicationsAnticholinergics(urinary tract disorders)Beta Adrenergic Agonists(asthma)Dopamine(Parkinsons disease)16C
7、auses Food and Drinks Carbonated beverages Chocolate Alcohol Citrus Fruits Coffee or Tea Fatty foods Containing tomatoes Mint Spicy Food 17Causes SmokingDamages mucus membranesImpairs muscle reflexes in the throatIncreases acid secretionReduces LES function and salivation 18Causes Obesity Laying dow
8、n after a large meal Eating close to bed time Exercise 19Release of Gastric Acid20Release 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 stomach21Treatme
9、nts Antacids Alginates Sucralfate Proton Pump Inhibitors Histamine H2-Recptor Antagonists Prokinetics New Treatments22Antacids Quick but short term Buffer gastric acid,increasing the pH Neutralize acid by the following reactionAl(OH)3+3 HCl AlCl3+3 H2O23AntacidsMaalox Al(OH)3(aluminum hydroxide),Mg(
10、OH)2(magnesium hydroxide)24Antacids Tums CaCO3(calcium carbonate)25AntacidsPepto-BismolC7H5BiO4(bismuth subsalicylate)26AntacidsAlka-SeltzerNaHCO3(sodium bicarbonate)27Alginates AlginatesUsually combined with an antacidForms protective barrier on top of gastric contentsGavisconSodium Alginate,Sodium
11、 Bicarbonate,and Calcium CarbonateLink28Alginates Polysaccharide found in the cell walls of brown algae Sodium alginate is the sodium salt of alginic acid29Alginic Acid30Sucralfate Reacts with stomach acid to from a cross linked viscous polymer that acts as an acid buffer Can bind to proteins on the
12、 surface of an ulcer to prevent further acid damage Has been shown to aid in healing by promoting epidermal growth factors and prostaglandins31Sucralfate(Carafate)32Proton Pump Inhibitors Proton pump inhibitors(PPIs)Inhibits the gastric acid pump,H+/K+ATPase Are prodrugs33PPIs Diffuse into the parie
13、tal 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 Link34Cysteine3536PPIsRabeprazol(Acipex)37PPIsLansoprazole(Pr
14、evacid)38PPIsEsomeprazole(Nexium)39PPIsOmeprazole(Prilosec)Omeprazole/sodium bicarbonate(Zegerid)40PPIs Pantoprazole(Protonix)41Treatments Histamine H2-recptor antagonists(H2RAs)The hormone,histamine stimulates the release of acid by interacting with the histamine receptor,or H2 receptor.Inhibit aci
15、d secretion by competitively and reversibly blocking parietal cell H2-receptors Less potent then PPIs42Agonist 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
16、agonist or natural messenger from binding43Histamine4445H2RAsCimetidine(Tagamet)46H2RAsNizatidine(Axid)47Other H2RAsRanitidine HCl(Zantac)Famotidine(Pepcid)48Treatments ProkineticsIncrease LES function Release stomach contents by Activating serotonin receptorsActing on dopaminergic receptors49Prokin
17、eticsMetoclopramide(Reglan,Degan)50ProkineticsDomperidone(Motilium,Costi)51ProkineticsCisapride(Prepulsid,Propulsid)52Prokinetics Rarely used because of severe side effects FatigueTremorsParkinsonismTardive DyskinesiaSevere cardiac events53New TreatmentsCholecystokinin2 receptor antagonists(CCK2)Pot
18、assium competitive acid blockers(P-CABs)54Treatments Cholecystokinin2 receptor antagonists (CCK2)Block the CCK2 receptors inhibiting acid secretionStill in clinical trialsBest use in combination with PPIs55CCK2Itriglumide56CCK2Z-36057Treatments Potassium competitive acid blockers(P-CABs)Target H+/K+
19、ATPaseIonically binds to the proton pumpSpecific for the K+binding region and prevents acid secretionBinds reversiblyStill in clinical trials58P-CABsRevaprazan59P-CABsSoraprazan60Treatment for H.pylori Amoxicillin+clarithromycin+proton pump inhibitor Metronidazole+clarithromycin+proton pump inhibito
20、r Bismuth subsalicylate+metronidazole+tetracycline+proton pump inhibitor61Assigned Reading Vesper,J.B.et all,Gastroesophageal Reflux Diesease,Is there More to the Story?,ChemMedChem(2008),3,552-559.62Homework Questions What is an antagonist and how do the H2RAs(histamine receptor antagonists)act as
21、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 G
22、ERD.Explain.63ReferencesBak,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
23、,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 643-671.64
