GERD胃食管反流英文版课件.ppt

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1、Agents to Treat Gastric Acidity and Gastroesophageal Reflux Disease(GERD)Presented byAbby RothOverview IntroductionSymptoms CausesPeptic Ulcer Disease H.pylori NSAIDsGERD TreatmentsWho is Affected?Gastric acidity and GERD affects people of all ages,races,and gender Symptoms Heartburn Acid Indigestio

2、n Regurgitation Nausea Symptoms Continued Hoarseness Sore Throat Chest Pain Bad Breath Dry Cough Asthma*Symptoms in Children Vomiting Coughing Breathing ProblemsAcid-Peptic Disorders Peptic Ulcer DiseaseOccurs when there is an imbalance between the mucosal defense factors and the acid and pepsin.Hel

3、icobacter 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 protectionH.pylori Produce large amounts of urease UreaseH203 NH3+CO2UreaH.pylori Secret proteins and toxins that interact with t

4、he stomachs epithelial cells Leads to inflammation and damageNSAIDs 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 Aff

5、ects 10 million Americans Approximately 7%have daily symptoms LinkGERD 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 CancerC

6、auses of GERD Abnormalities with the Lower Esophageal Sphincter,or LES Stomach AbnormalitiesHiatal herniaLinkCauses MedicationsNSAIDsCalcium Channel Blockers(high blood pressure,angina)MedicationsAnticholinergics(urinary tract disorders)Beta Adrenergic Agonists(asthma)Dopamine(Parkinsons disease)Cau

7、ses Food and Drinks Carbonated beverages Chocolate Alcohol Citrus Fruits Coffee or Tea Fatty foods Containing tomatoes Mint Spicy Food Causes SmokingDamages mucus membranesImpairs muscle reflexes in the throatIncreases acid secretionReduces LES function and salivation Causes Obesity Laying down afte

8、r a large meal Eating close to bed time Exercise Release of Gastric AcidRelease 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 stomachTreatments Antacids

9、 Alginates Sucralfate Proton Pump Inhibitors Histamine H2-Recptor Antagonists Prokinetics New TreatmentsAntacids Quick but short term Buffer gastric acid,increasing the pH Neutralize acid by the following reactionAl(OH)3+3 HCl AlCl3+3 H2OAntacidsMaalox Al(OH)3(aluminum hydroxide),Mg(OH)2(magnesium h

10、ydroxide)Antacids Tums CaCO3(calcium carbonate)AntacidsPepto-BismolC7H5BiO4(bismuth subsalicylate)AntacidsAlka-SeltzerNaHCO3(sodium bicarbonate)Alginates AlginatesUsually combined with an antacidForms protective barrier on top of gastric contentsGavisconSodium Alginate,Sodium Bicarbonate,and Calcium

11、 CarbonateLinkAlginates Polysaccharide found in the cell walls of brown algae Sodium alginate is the sodium salt of alginic acidAlginic AcidSucralfate 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 preven

12、t further acid damage Has been shown to aid in healing by promoting epidermal growth factors and prostaglandinsSucralfate(Carafate)Proton Pump Inhibitors Proton pump inhibitors(PPIs)Inhibits the gastric acid pump,H+/K+ATPase Are prodrugsPPIs Diffuse into the parietal cells of the stomach and accumul

13、ates 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 LinkCysteinePPIsRabeprazol(Acipex)PPIsLansoprazole(Prevacid)PPIsEsomeprazole(Nexium)PPIsOmeprazol

14、e(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

15、 parietal cell H2-receptors Less potent then PPIsAgonist 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 bindingHistamineH2RA

16、sCimetidine(Tagamet)H2RAsNizatidine(Axid)Other H2RAsRanitidine HCl(Zantac)Famotidine(Pepcid)Treatments ProkineticsIncrease LES function Release stomach contents by Activating serotonin receptorsActing on dopaminergic receptorsProkineticsMetoclopramide(Reglan,Degan)ProkineticsDomperidone(Motilium,Cos

17、ti)ProkineticsCisapride(Prepulsid,Propulsid)Prokinetics Rarely used because of severe side effects FatigueTremorsParkinsonismTardive DyskinesiaSevere cardiac eventsNew TreatmentsCholecystokinin2 receptor antagonists(CCK2)Potassium competitive acid blockers(P-CABs)Treatments Cholecystokinin2 receptor

18、 antagonists (CCK2)Block the CCK2 receptors inhibiting acid secretionStill in clinical trialsBest use in combination with PPIsCCK2ItriglumideCCK2Z-360Treatments Potassium competitive acid blockers(P-CABs)Target H+/K+ATPaseIonically binds to the proton pumpSpecific for the K+binding region and preven

19、ts acid secretionBinds reversiblyStill in clinical trialsP-CABsRevaprazanP-CABsSoraprazanTreatment for H.pylori Amoxicillin+clarithromycin+proton pump inhibitor Metronidazole+clarithromycin+proton pump inhibitor Bismuth subsalicylate+metronidazole+tetracycline+proton pump inhibitorAssigned Reading V

20、esper,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,includin

21、g 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 GERD.Explain.ReferencesBak,Young-Tae.Management Strategies for Gastroesophageal Reflux Disease.

22、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.

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