1、Overview IntroductionSymptoms CausesPeptic Ulcer Disease H.pylori NSAIDsGERD Treatments1GERD讲解胃食管反流英文11/3/2022Who is Affected?Gastric acidity and GERD affects people of all ages,races,and gender 2GERD讲解胃食管反流英文11/3/2022Symptoms Heartburn Acid Indigestion Regurgitation Nausea 3GERD讲解胃食管反流英文11/3/2022Sy
2、mptoms Continued Hoarseness Sore Throat Chest Pain Bad Breath Dry Cough Asthma*4GERD讲解胃食管反流英文11/3/2022Symptoms in Children Vomiting Coughing Breathing Problems5GERD讲解胃食管反流英文11/3/2022Acid-Peptic Disorders Peptic Ulcer DiseaseOccurs when there is an imbalance between the mucosal defense factors and th
3、e acid and pepsin.6GERD讲解胃食管反流英文11/3/2022Helicobacter 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 protection7GERD讲解胃食管反流英文11/3/2022H.pylori Produce large amounts of urease UreaseH203
4、NH3+CO2Urea8GERD讲解胃食管反流英文11/3/2022H.pylori Secret proteins and toxins that interact with the stomachs epithelial cells Leads to inflammation and damage9GERD讲解胃食管反流英文11/3/2022NSAIDs Aspirin,Ibuprofen,Naproxen Can have an affect at very low doses Suppresses cylooxygenase-1 Decrease production of prost
5、aglandins 10GERD讲解胃食管反流英文11/3/2022What 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 Link11GERD讲解胃食管反流英文11/3/2022GERD vs.NERD Patients suffering symptoms are placed in two groups Non-ero
6、sive reflux disease,or NERDErosive esophagitis Erosive esophagitis is characterized by swelling and InflammationBarretts EsophagusPrecursor to Esophageal Cancer12GERD讲解胃食管反流英文11/3/2022Causes of GERD Abnormalities with the Lower Esophageal Sphincter,or LES Stomach AbnormalitiesHiatal herniaLink13GERD
7、讲解胃食管反流英文11/3/2022Causes MedicationsNSAIDsCalcium Channel Blockers(high blood pressure,angina)14GERD讲解胃食管反流英文11/3/2022MedicationsAnticholinergics(urinary tract disorders)Beta Adrenergic Agonists(asthma)Dopamine(Parkinsons disease)15GERD讲解胃食管反流英文11/3/2022Causes Food and Drinks Carbonated beverages Ch
8、ocolate Alcohol Citrus Fruits Coffee or Tea Fatty foods Containing tomatoes Mint Spicy Food 16GERD讲解胃食管反流英文11/3/2022Causes SmokingDamages mucus membranesImpairs muscle reflexes in the throatIncreases acid secretionReduces LES function and salivation 17GERD讲解胃食管反流英文11/3/2022Causes Obesity Laying down
9、 after a large meal Eating close to bed time Exercise 18GERD讲解胃食管反流英文11/3/2022Release of Gastric Acid19GERD讲解胃食管反流英文11/3/2022Release of Gastric acid Histamine stimulates acid release by interacting with the histamine receptor,H2 Acetylcholine activates the cholinergic receptors Gastrin is released w
10、hen food is present in the stomach20GERD讲解胃食管反流英文11/3/2022Treatments Antacids Alginates Sucralfate Proton Pump Inhibitors Histamine H2-Recptor Antagonists Prokinetics New Treatments21GERD讲解胃食管反流英文11/3/2022Antacids Quick but short term Buffer gastric acid,increasing the pH Neutralize acid by the foll
11、owing reactionAl(OH)3+3 HCl AlCl3+3 H2O22GERD讲解胃食管反流英文11/3/2022AntacidsMaalox Al(OH)3(aluminum hydroxide),Mg(OH)2(magnesium hydroxide)23GERD讲解胃食管反流英文11/3/2022Antacids Tums CaCO3(calcium carbonate)24GERD讲解胃食管反流英文11/3/2022AntacidsPepto-BismolC7H5BiO4(bismuth subsalicylate)25GERD讲解胃食管反流英文11/3/2022Antac
12、idsAlka-SeltzerNaHCO3(sodium bicarbonate)26GERD讲解胃食管反流英文11/3/2022Alginates AlginatesUsually combined with an antacidForms protective barrier on top of gastric contentsGavisconSodium Alginate,Sodium Bicarbonate,and Calcium CarbonateLink27GERD讲解胃食管反流英文11/3/2022Alginates Polysaccharide found in the cel
13、l walls of brown algae Sodium alginate is the sodium salt of alginic acid28GERD讲解胃食管反流英文11/3/2022Alginic Acid29GERD讲解胃食管反流英文11/3/2022Sucralfate 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 furth
14、er acid damage Has been shown to aid in healing by promoting epidermal growth factors and prostaglandins30GERD讲解胃食管反流英文11/3/2022Sucralfate(Carafate)31GERD讲解胃食管反流英文11/3/2022Proton Pump Inhibitors Proton pump inhibitors(PPIs)Inhibits the gastric acid pump,H+/K+ATPase Are prodrugs32GERD讲解胃食管反流英文11/3/20
15、22PPIs 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 Link33GERD讲解胃食管反流英文11/3/2022Cyst
16、eine34GERD讲解胃食管反流英文11/3/202235GERD讲解胃食管反流英文11/3/2022PPIsRabeprazol(Acipex)36GERD讲解胃食管反流英文11/3/2022PPIsLansoprazole(Prevacid)37GERD讲解胃食管反流英文11/3/2022PPIsEsomeprazole(Nexium)38GERD讲解胃食管反流英文11/3/2022PPIsOmeprazole(Prilosec)Omeprazole/sodium bicarbonate(Zegerid)39GERD讲解胃食管反流英文11/3/2022PPIs Pantoprazole(
17、Protonix)40GERD讲解胃食管反流英文11/3/2022Treatments 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 the
18、n PPIs41GERD讲解胃食管反流英文11/3/2022Agonist 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 binding42GERD讲解胃食管反流英文11/3/2022Histamin
19、e43GERD讲解胃食管反流英文11/3/202244GERD讲解胃食管反流英文11/3/2022H2RAsCimetidine(Tagamet)45GERD讲解胃食管反流英文11/3/2022H2RAsNizatidine(Axid)46GERD讲解胃食管反流英文11/3/2022Other H2RAsRanitidine HCl(Zantac)Famotidine(Pepcid)47GERD讲解胃食管反流英文11/3/2022Treatments ProkineticsIncrease LES function Release stomach contents by Activating
20、serotonin receptorsActing on dopaminergic receptors48GERD讲解胃食管反流英文11/3/2022ProkineticsMetoclopramide(Reglan,Degan)49GERD讲解胃食管反流英文11/3/2022ProkineticsDomperidone(Motilium,Costi)50GERD讲解胃食管反流英文11/3/2022ProkineticsCisapride(Prepulsid,Propulsid)51GERD讲解胃食管反流英文11/3/2022Prokinetics Rarely used because of
21、severe side effects FatigueTremorsParkinsonismTardive DyskinesiaSevere cardiac events52GERD讲解胃食管反流英文11/3/2022New TreatmentsCholecystokinin2 receptor antagonists(CCK2)Potassium competitive acid blockers(P-CABs)53GERD讲解胃食管反流英文11/3/2022Treatments Cholecystokinin2 receptor antagonists (CCK2)Block the CC
22、K2 receptors inhibiting acid secretionStill in clinical trialsBest use in combination with PPIs54GERD讲解胃食管反流英文11/3/2022CCK2Itriglumide55GERD讲解胃食管反流英文11/3/2022CCK2Z-36056GERD讲解胃食管反流英文11/3/2022Treatments Potassium competitive acid blockers(P-CABs)Target H+/K+ATPaseIonically binds to the proton pumpSpe
23、cific for the K+binding region and prevents acid secretionBinds reversiblyStill in clinical trials57GERD讲解胃食管反流英文11/3/2022P-CABsRevaprazan58GERD讲解胃食管反流英文11/3/2022P-CABsSoraprazan59GERD讲解胃食管反流英文11/3/2022Treatment for H.pylori Amoxicillin+clarithromycin+proton pump inhibitor Metronidazole+clarithromyc
24、in+proton pump inhibitor Bismuth subsalicylate+metronidazole+tetracycline+proton pump inhibitor60GERD讲解胃食管反流英文11/3/2022Assigned Reading Vesper,J.B.et all,Gastroesophageal Reflux Diesease,Is there More to the Story?,ChemMedChem(2008),3,552-559.61GERD讲解胃食管反流英文11/3/2022Homework Questions What is an ant
25、agonist 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 PPIs to become
26、 an active drug?Bacteria in the upper GI tract may play a role in GERD.Explain.62GERD讲解胃食管反流英文11/3/2022ReferencesBak,Young-Tae.Management Strategies for Gastroesophageal Reflux Disease.Journal of Gastroenterology and Hepatology(2004),19,S49-S53.Horn,J.Understanding the Pharmacodynamic and Pharmacoki
27、netic 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 643-671.63GERD讲解胃食管反流英文11/3/2022
