胃食管反流英文版课件

1、Agents to Treat Gastric Acidity and Gastroesophageal Reflux Disease(GERD)1Agents to Treat Gastric AciditOverviewIntroductionSymptomsCausesPeptic Ulcer DiseaseH. pyloriNSAIDsGERDTreatments2OverviewIntroduction2Who is Affected?Gastric acidity and GERD affects people of all ages, races, and gender 3Who

2、 is Affected?Gastric aciditSymptomsHeartburnAcid IndigestionRegurgitationNausea 4SymptomsHeartburnRegurgitationSymptoms ContinuedHoarsenessSore ThroatChest PainBad BreathDry CoughAsthma*5Symptoms ContinuedHoarseness5Symptoms in ChildrenVomiting CoughingBreathing Problems6Symptoms in ChildrenVomiting

3、 6Acid-Peptic DisordersPeptic Ulcer DiseaseOccurs when there is an imbalance between the mucosal defense factors and the acid and pepsin.7Acid-Peptic DisordersPeptic UlHelicobacter pylori InfectionCauses 80% of peptic ulcersSurvives the acid environment by attaching to the sugar molecules that line

4、the stomach wallUses the mucus layer as protection8Helicobacter pylori InfectionCH. pyloriProduce large amounts of urease UreaseH203 NH3 + CO2Urea9H. pyloriProduce large amountsH. pyloriSecret proteins and toxins that interact with the stomachs epithelial cellsLeads to inflammation and damage10H. py

5、loriSecret proteins and tNSAIDsAspirin, Ibuprofen, NaproxenCan have an affect at very low dosesSuppresses cylooxygenase-1 Decrease production of prostaglandins 11NSAIDsAspirin, Ibuprofen, NaprWhat is GERD?Condition where the stomach acid/content is pushed back or “refluxed” into the esophagusAffects

6、 10 million AmericansApproximately 7% have daily symptomsLink12What 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 EsophagusPrec

7、ursor to Esophageal Cancer13GERD vs. NERDPatients sufferinCauses of GERDAbnormalities with the Lower Esophageal Sphincter, or LESStomach AbnormalitiesHiatal herniaLink14Causes of GERDAbnormalities wiCauses MedicationsNSAIDsCalcium Channel Blockers (high blood pressure, angina)15Causes Medications15M

8、edicationsAnticholinergics (urinary tract disorders)Beta Adrenergic Agonists (asthma)Dopamine (Parkinsons disease)16MedicationsAnticholinergics (uCausesFood and DrinksCarbonated beveragesChocolate AlcoholCitrus FruitsCoffee or TeaFatty foodsContaining tomatoesMintSpicy Food 17CausesFood and Drinks17

9、CausesSmokingDamages mucus membranesImpairs muscle reflexes in the throatIncreases acid secretionReduces LES function and salivation 18CausesSmoking18CausesObesityLaying down after a large mealEating close to bed timeExercise 19CausesObesity19Release of Gastric Acid20Release of Gastric Acid20Release

10、 of Gastric acidHistamine stimulates acid release by interacting with the histamine receptor, H2Acetylcholine activates the cholinergic receptorsGastrin is released when food is present in the stomach21Release of Gastric acidHistamiTreatmentsAntacidsAlginatesSucralfateProton Pump InhibitorsHistamine

11、 H2-Recptor AntagonistsProkineticsNew Treatments22TreatmentsAntacids22AntacidsQuick but short termBuffer gastric acid, increasing the pHNeutralize acid by the following reactionAl(OH)3 + 3 HCl AlCl3 + 3 H2O23AntacidsQuick but short term23AntacidsMaalox Al(OH)3 (aluminum hydroxide), Mg(OH)2 (magnesiu

12、m hydroxide)24AntacidsMaalox 24AntacidsTums CaCO3 (calcium carbonate)25AntacidsTums 25AntacidsPepto-BismolC7H5BiO4 (bismuth subsalicylate)26AntacidsPepto-Bismol26AntacidsAlka-SeltzerNaHCO3 (sodium bicarbonate)27AntacidsAlka-Seltzer27AlginatesAlginatesUsually combined with an antacidForms protective

13、barrier on top of gastric contentsGavisconSodium Alginate, Sodium Bicarbonate, and Calcium CarbonateLink28AlginatesAlginates28AlginatesPolysaccharide found in the cell walls of brown algaeSodium alginate is the sodium salt of alginic acid29AlginatesPolysaccharide found Alginic Acid30Alginic Acid30Su

14、cralfateReacts with stomach acid to from a cross linked viscous 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 prostaglandins31SucralfateReacts with stomach Su

15、cralfate (Carafate)32Sucralfate (Carafate)32Proton Pump InhibitorsProton pump inhibitors (PPIs) Inhibits the gastric acid pump, H+/K+ ATPase Are prodrugs33Proton Pump InhibitorsProton pPPIs Diffuse into the parietal cells of the stomach and accumulatesActivated by proton-catalyzed formation of sulfe

16、nic acidThis prevents the drug from diffusing outActivated form then irreversibly binds at the sulfhydryl groups of the cysteins of the H+/K+ ATPaseLink34PPIs Diffuse into the parietalCysteine35Cysteine353636PPIsRabeprazol (Acipex)37PPIsRabeprazol (Acipex)37PPIsLansoprazole (Prevacid)38PPIsLansopraz

17、ole (Prevacid)38PPIsEsomeprazole (Nexium)39PPIsEsomeprazole (Nexium)39PPIsOmeprazole (Prilosec)Omeprazole/sodium bicarbonate (Zegerid)40PPIsOmeprazole (Prilosec)OmeprPPIs Pantoprazole (Protonix)41PPIs Pantoprazole (Protonix)41TreatmentsHistamine H2-recptor antagonists (H2RAs)The hormone, histamine s

18、timulates the release of acid by interacting with the histamine receptor, or H2 receptor.Inhibit acid secretion by competitively and reversibly blocking parietal cell H2-receptorsLess potent then PPIs42TreatmentsHistamine H2-recptorAgonist vs. AntagonistAn agonist is a drug that produces the same re

19、sponse at a receptor as the natural messengerAn antagonist is a drug which binds to a receptor without activating it, prevent an agonist or natural messenger from binding43Agonist vs. AntagonistAn agoniHistamine44Histamine444545H2RAsCimetidine (Tagamet) 46H2RAsCimetidine (Tagamet) 46H2RAsNizatidine

20、(Axid)47H2RAsNizatidine (Axid)47Other H2RAsRanitidine HCl (Zantac)Famotidine (Pepcid) 48Other H2RAsRanitidine HCl (ZanTreatmentsProkineticsIncrease LES function Release stomach contents by Activating serotonin receptorsActing on dopaminergic receptors49TreatmentsProkinetics49ProkineticsMetoclopramid

21、e (Reglan, Degan)50ProkineticsMetoclopramide (RegProkineticsDomperidone (Motilium, Costi)51ProkineticsDomperidone (MotiliProkineticsCisapride (Prepulsid, Propulsid)52ProkineticsCisapride (PrepulsiProkineticsRarely used because of severe side effects FatigueTremorsParkinsonismTardive DyskinesiaSevere

22、 cardiac events53ProkineticsRarely used becausNew TreatmentsCholecystokinin2 receptor antagonists (CCK2)Potassium competitive acid blockers (P-CABs)54New TreatmentsCholecystokinin2TreatmentsCholecystokinin2 receptor antagonists (CCK2)Block the CCK2 receptors inhibiting acid secretionStill in clinica

23、l trialsBest use in combination with PPIs55TreatmentsCholecystokinin2 recCCK2Itriglumide56CCK2Itriglumide56CCK2Z-36057CCK2Z-36057TreatmentsPotassium competitive acid blockers (P-CABs)Target H+/K+ ATPaseIonically binds to the proton pumpSpecific for the K+ binding region and prevents acid secretionBi

24、nds reversiblyStill in clinical trials58TreatmentsPotassium competitivP-CABsRevaprazan59P-CABsRevaprazan59P-CABsSoraprazan60P-CABsSoraprazan60Treatment for H. pyloriAmoxicillin + clarithromycin + proton pump inhibitorMetronidazole + clarithromycin + proton pump inhibitorBismuth subsalicylate + metro

25、nidazole + tetracycline + proton pump inhibitor61Treatment for H. pyloriAmoxiciAssigned ReadingVesper, J.B. et all, Gastroesophageal Reflux Diesease, Is there More to the Story?, ChemMedChem (2008), 3, 552-559.62Assigned 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 prodru