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1、Agents to Treat Gastric Acidity and Gastroesophageal Reflux Disease(GERD)Presented byAbby RothAgents to Treat Gastric AciditOverviewIntroductionSymptomsCausesPeptic Ulcer DiseaseH. pyloriNSAIDsGERDTreatmentsOverviewIntroductionWho is Affected?Gastric acidity and GERD affects people of all ages, race
2、s, and gender Who is Affected?Gastric aciditSymptomsHeartburnAcid IndigestionRegurgitationNausea SymptomsHeartburnRegurgitationSymptoms ContinuedHoarsenessSore ThroatChest PainBad BreathDry CoughAsthma*Symptoms ContinuedHoarsenessSymptoms in ChildrenVomiting CoughingBreathing ProblemsSymptoms in Chi
3、ldrenVomiting Acid-Peptic DisordersPeptic Ulcer DiseaseOccurs when there is an imbalance between the mucosal defense factors and the acid and pepsin.Acid-Peptic DisordersPeptic UlHelicobacter pylori InfectionCauses 80% of peptic ulcersSurvives the acid environment by attaching to the sugar molecules
4、 that line the stomach wallUses the mucus layer as protectionHelicobacter pylori InfectionCH. pyloriProduce large amounts of urease UreaseH203 NH3 + CO2UreaH. pyloriProduce large amountsH. pyloriSecret proteins and toxins that interact with the stomachs epithelial cellsLeads to inflammation and dama
5、geH. pyloriSecret proteins and tNSAIDsAspirin, Ibuprofen, NaproxenCan have an affect at very low dosesSuppresses cylooxygenase-1 Decrease production of prostaglandins NSAIDsAspirin, Ibuprofen, NaprWhat is GERD?Condition where the stomach acid/content is pushed back or “refluxed” into the esophagusAf
6、fects 10 million AmericansApproximately 7% have daily symptomsLinkWhat is GERD?Condition where tGERD vs. NERDPatients suffering symptoms are placed in two groups Non-erosive reflux disease, or NERDErosive esophagitisErosive esophagitis is characterized by swelling and InflammationBarretts EsophagusP
7、recursor to Esophageal CancerGERD vs. NERDPatients sufferinCauses of GERDAbnormalities with the Lower Esophageal Sphincter, or LESStomach AbnormalitiesHiatal herniaLinkCauses of GERDAbnormalities wiCauses MedicationsNSAIDsCalcium Channel Blockers (high blood pressure, angina)Causes MedicationsMedica
8、tionsAnticholinergics (urinary tract disorders)Beta Adrenergic Agonists (asthma)Dopamine (Parkinsons disease)MedicationsAnticholinergics (uCausesFood and DrinksCarbonated beveragesChocolate AlcoholCitrus FruitsCoffee or TeaFatty foodsContaining tomatoesMintSpicy Food CausesFood and DrinksCausesSmoki
9、ngDamages mucus membranesImpairs muscle reflexes in the throatIncreases acid secretionReduces LES function and salivation CausesSmokingCausesObesityLaying down after a large mealEating close to bed timeExercise CausesObesityRelease of Gastric AcidRelease of Gastric AcidRelease of Gastric acidHistami
10、ne stimulates acid release by interacting with the histamine receptor, H2Acetylcholine activates the cholinergic receptorsGastrin is released when food is present in the stomachRelease of Gastric acidHistamiTreatmentsAntacidsAlginatesSucralfateProton Pump InhibitorsHistamine H2-Recptor AntagonistsPr
11、okineticsNew TreatmentsTreatmentsAntacidsAntacidsQuick but short termBuffer gastric acid, increasing the pHNeutralize acid by the following reactionAl(OH)3 + 3 HCl AlCl3 + 3 H2OAntacidsQuick but short termAntacidsMaalox Al(OH)3 (aluminum hydroxide), Mg(OH)2 (magnesium hydroxide)AntacidsMaalox Antaci
12、dsTums CaCO3 (calcium carbonate)AntacidsTums AntacidsPepto-BismolC7H5BiO4 (bismuth subsalicylate)AntacidsPepto-BismolAntacidsAlka-SeltzerNaHCO3 (sodium bicarbonate)AntacidsAlka-SeltzerAlginatesAlginatesUsually combined with an antacidForms protective barrier on top of gastric contentsGavisconSodium
13、Alginate, Sodium Bicarbonate, and Calcium CarbonateLinkAlginatesAlginatesAlginatesPolysaccharide found in the cell walls of brown algaeSodium alginate is the sodium salt of alginic acidAlginatesPolysaccharide found Alginic AcidAlginic AcidSucralfateReacts with stomach acid to from a cross linked vis
14、cous polymer that acts as an acid bufferCan bind to proteins on the surface of an ulcer to prevent further acid damageHas been shown to aid in healing by promoting epidermal growth factors and prostaglandinsSucralfateReacts with stomach Sucralfate (Carafate)Sucralfate (Carafate)Proton Pump Inhibitor
15、sProton pump inhibitors (PPIs) Inhibits the gastric acid pump, H+/K+ ATPase Are prodrugsProton Pump InhibitorsProton pPPIs Diffuse into the parietal cells of the stomach and accumulatesActivated by proton-catalyzed formation of sulfenic acidThis prevents the drug from diffusing outActivated form the
16、n irreversibly binds at the sulfhydryl groups of the cysteins of the H+/K+ ATPaseLinkPPIs Diffuse into the parietalCysteineCysteineGERD_胃食管反流英文版课件PPIsRabeprazol (Acipex)PPIsRabeprazol (Acipex)PPIsLansoprazole (Prevacid)PPIsLansoprazole (Prevacid)PPIsEsomeprazole (Nexium)PPIsEsomeprazole (Nexium)PPIs
17、Omeprazole (Prilosec)Omeprazole/sodium bicarbonate (Zegerid)PPIsOmeprazole (Prilosec)OmeprPPIs Pantoprazole (Protonix)PPIs Pantoprazole (Protonix)TreatmentsHistamine H2-recptor antagonists (H2RAs)The hormone, histamine stimulates the release of acid by interacting with the histamine receptor, or H2
18、receptor.Inhibit acid secretion by competitively and reversibly blocking parietal cell H2-receptorsLess potent then PPIsTreatmentsHistamine H2-recptorAgonist vs. AntagonistAn agonist is a drug that produces the same response at a receptor as the natural messengerAn antagonist is a drug which binds t
19、o a receptor without activating it, prevent an agonist or natural messenger from bindingAgonist vs. AntagonistAn agoniHistamineHistamineGERD_胃食管反流英文版课件H2RAsCimetidine (Tagamet) H2RAsCimetidine (Tagamet) H2RAsNizatidine (Axid)H2RAsNizatidine (Axid)Other H2RAsRanitidine HCl (Zantac)Famotidine (Pepcid)
20、 Other H2RAsRanitidine HCl (ZanTreatmentsProkineticsIncrease LES function Release stomach contents by Activating serotonin receptorsActing on dopaminergic receptorsTreatmentsProkineticsProkineticsMetoclopramide (Reglan, Degan)ProkineticsMetoclopramide (RegProkineticsDomperidone (Motilium, Costi)Prok
21、ineticsDomperidone (MotiliProkineticsCisapride (Prepulsid, Propulsid)ProkineticsCisapride (PrepulsiProkineticsRarely used because of severe side effects FatigueTremorsParkinsonismTardive DyskinesiaSevere cardiac eventsProkineticsRarely used becausNew TreatmentsCholecystokinin2 receptor antagonists (
22、CCK2)Potassium competitive acid blockers (P-CABs)New TreatmentsCholecystokinin2TreatmentsCholecystokinin2 receptor antagonists (CCK2)Block the CCK2 receptors inhibiting acid secretionStill in clinical trialsBest use in combination with PPIsTreatmentsCholecystokinin2 recCCK2ItriglumideCCK2Itriglumide
23、CCK2Z-360CCK2Z-360TreatmentsPotassium competitive acid blockers (P-CABs)Target H+/K+ ATPaseIonically binds to the proton pumpSpecific for the K+ binding region and prevents acid secretionBinds reversiblyStill in clinical trialsTreatmentsPotassium competitivP-CABsRevaprazanP-CABsRevaprazanP-CABsSorap
24、razanP-CABsSoraprazanTreatment for H. pyloriAmoxicillin + clarithromycin + proton pump inhibitorMetronidazole + clarithromycin + proton pump inhibitorBismuth subsalicylate + metronidazole + tetracycline + proton pump inhibitorTreatment for H. pyloriAmoxiciAssigned ReadingVesper, J.B. et all, Gastroe
25、sophageal Reflux Diesease, Is there More to the Story?, ChemMedChem (2008), 3, 552-559.Assigned ReadingVesper, J.B. eHomework QuestionsWhat 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 c
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