Gastroenterology: Peptic Ulcer Disease - PowerPoint Presentation

1. Gastroenterology:Peptic Ulcer DiseaseCourses in Therapeutics and Disease State Management

2. Learning ObjectivesIdentify and compare the common forms of peptic ulcer disease (PUD).Describe features associated with Helicobactor pylori-associated and NSAID-induced ulcers.Discuss the role of Helicobacter pylori (HP) in PUD.Compare and contrast signs and symptoms of duodenal and gastric ulcers.Identify, describe, and discuss the utility of laboratory tests used to detect the presence of HP

3. Learning ObjectivesDiscuss pharmacologic treatment options for HP-associated and NSAID-induced PUD.Given a PUD patient history, recommend appropriate pharmacologic therapy and explain the rationale behind your decisionDiscuss drug adverse effects and monitoring parameters for drugs and disease statesConstruct counseling points for a PUD patient on their disease state and pharmacologic therapy

4. Required ReadingLove BL, Mohorn PL. Peptic Ulcer Disease and Related Disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; 2017.

5. OverviewPeptic ulcer disease (PUD) refers to ulceration of the mucosa anywhere in the GI tract exposed to acid and pepsinThey can range in size from a few millimeters to a few centimetersEstimated that 10% of Americans will develop PUD in their lifetimeThe 2 most common forms/locations of PUD areDuodenal ulcerGastric ulcer

6. Duodenal UlcersMost common form of PUDIt is 3 times more common than gastric ulcersUsually located in the duodenal bulb of the small intestineMost commonly occurs in people between the ages of 30 and 50

7. Gastric UlcersLess common than duodenal ulcersEspecially in the absence of chronic NSAID useMost commonly located in the lesser curvature of the antrum of the stomachMore common in people greater than 60 years old

8. Duodenal and Gastric UlcersLink: Anatomic structure of the stomach and duodenum and most common locations of gastric and duodenal ulcers.

9. Duodenal and Gastric UlcersLink: Figure of a Duodenal UlcerLink: Figure of a Duodenal Ulcer and a Gastric Ulcer

10. Etiology and PathophysiologyGastric and duodenal ulcers develop because of an imbalance between aggressive factors and mechanisms that maintain mucosal integrityThere is an increase in mucosal injury and a decrease in mucosal defenseAggressive factors (H. pylori, NSAIDs) cause mucosal injury and a decrease in mucosal defenses and healing (decreased mucous, decreased bicarbonate, decreased mucosal blood flow)

11. Etiology and PathophysiologyCommon causes of PUDHelicobacter pylori (H.pylori) infectionNonsteroidal Anti-inflammatory Drugs (NSAIDs)Critical illness (stress-related mucosal damage)Uncommon causes of PUDIdiopathic (non-H.pylori, non- NSAID)Hypersecretion of gastric acid (e.g. Zollinger Ellison syndrome)Viral infectionsRadiation therapyChemotherapy

12. Helicobacter Pylori (HP)-AssociatedHelicobacter pylori (HP) is a spiral shaped, gram negative, flagellated bacteria first associated with PUD in the early 1980’sFound in most people with duodenal and gastric ulcersAbout 95% of those with duodenal ulcersAbout 80% of those with gastric ulcers

13. Helicobacter Pylori (HP)-AssociatedApproximately 30% - 40% of the U.S. population is infectedAbout 15% of those infected will develop PUDHP is primarily spread through the fecal to oral routePeople are most often infected during childhood

14. Helicobacter Pylori (HP)-AssociatedMechanisms by which HP causes mucosal injury are not entirely clear but occurs through a combination of the following mechanisms:HP catalyzes urea  ammonia is produced  ammonia erodes the mucous barrier and causes epithelial damageHP produces cytotoxinsHP produces mucolytic enzymes

15. Helicobacter pylori (HP)-AssociatedLink: Schematic of the relationships between colonization with Helicobacter pylori and diseases of the upper gastrointestinal tract

16. NSAID-InducedIn long-term NSAID users, there is a 10% - 20% prevalence of gastric ulcers and a 2% - 5% prevalence of duodenal ulcersMechanisms for NSAID-induced ulcerationNSAIDs are weak acids and are non-ionized at gastric pHDiffuse freely across the mucous barrier into gastric epithelial cells  H+ ions are liberated and cause cellular damage

17. NSAID-InducedMechanisms for NSAID-induced ulceration (continued)NSAIDs inhibit cyclooxygenase activity and therefore decrease prostaglandin production which results in a:Reduction in gastric and mucosal blood flowDecrease in mucous and bicarbonate secretionDecrease in cellular repair and replicationLink: Figure showing mechanisms by which nonsteroidal anti-inflammatory drugs may induce mucosal injury

18. NSAID-Induced1% - 2% of NSAID users will develop an ulcer or ulcer complications with 1 yearThe risk of developing an NSAID-related complication is greater in patients:Greater than 60 years oldWith a prior history of PUDTaking high dose NSAIDs or multiple NSAIDs, including low dose aspirin

19. NSAID-InducedThe risk of developing an NSAID-related complication is greater in patients (continued):Who are concurrently takingCorticosteroidsAnticoagulantsOral bisphosphonatesAnti-platelet agentsSSRIs (Selective Serotonin Reuptake Inhibitors)Aspirin is the most ulcernogenic of all NSAIDs.Even with low dose aspirin (81-162mg/day), ulcers occur in 0.6% - 1.2% of patients per year.

20. Zollinger-Ellison Syndrome (ZES)ZES is characterized by gastric acid hypersecretion and recurrent peptic ulcers that result from a gastrin-producing tumorMore than 50% of gastrinomas are malignantZES is suspected for patients with multiple ulcers and recurrent or refractory PUD often accompanied by esophagitis or ulcer complicationsOnly accounts for 0.1% to 1% of those with duodenal ulcer

21. Other Potential Factors in the Development of PUDCigarette smokingIncreases the risk of developing PUD and its complicationsImpairs ulcer healing and increases the risk of recurrenceUlcer risk is proportional to the number of cigarettes smoked per dayPsychological stressPeople who develop PUD tend to be more adversely affected by stressHowever, controlled trials are conflicting and have failed to document a direct cause-effect relationshipStress may induce behavioral risks such as smoking and the use of NSAIDs or may alter the inflammatory response or resistance to HP infectionDietary factorsCertain foods (e.g. coffee, tea, carbonated beverages, beer, milk, spices) may cause dyspepsia but do not increase the risk of developing PUD

22. Signs and SymptomsSymptoms depend on ulcer location, ulcer etiology, and patient ageMany patients, particularly the elderly, have few or even no symptomsNSAID-induced ulcers are often silentComplications such as bleeding and perforation are often the initial presentation

23. Signs and SymptomsPain localized to the epigastrium is the most common symptomThe pain is described as burning, gnawing, cramping, or hungerA typical nocturnal pain that wakes the patient from sleep (especially between 12 and 3am)The severity of ulcer pain varies from patient to patient and my be seasonal, occurring more often in the spring or fall

24. Signs and SymptomsEpisodes of pain usually occur in clusters, lasting up to a few weeks followed by a pain-free period or remission lasting weeks to yearsChanges in the character of pain may suggest the presence of complicationsPyrosis (heartburn), belching, and bloating may accompany the pain

25. Gastric UlcerPain often does not follow a consistent pattern; not predictableFood will sometimes cause or accentuate painNausea, vomiting, anorexia, and weight loss are more common with gastric ulcer than duodenal ulcer

26. Duodenal UlcerPain more likely follows a consistent pattern (compared to gastric ulcer)Epigastric pain occurs in 60% - 90% of patients with duodenal ulcersFood often relieves pain but the pain usually returns 1 to 3 hours after eatingNocturnal epigastric pain often occurs40% - 70% have additional non-specific dyspeptic complaints (belching, bloating, abdominal distension, food intolerance)

27. Clinical PresentationLink: Table on Comparison of Common Forms of Peptic UlcerLink: Table on Clinical Presentation of Peptic Ulcer Disease

28. ComplicationsMajor complications of PUD include:BleedingOccurs in about 15% of patients with active PUDPerforationOccurs in about 7% of patients with active PUDMortalityMortality from acute bleeding is about 6% - 10%

29. Bleeding and Hemorrhage in Peptic UlcersLink: Figure of stigmata of hemorrhage in peptic ulcers

30. Role of TestingThe diagnosis of PUD depends on visualizing the ulcer crater by either upper GI radiography or upper endoscopyUpper GI radiography with barium was the initial diagnostic procedure but has been replaced with upper endoscopyThere are multiple laboratory tests that can be performed to diagnosis an H.pylori infection

31. Testing for H. pyloriThere are multiple tests that can be performed to test for the presence of H. pyloriInvasive testing (Requires endoscopy with biopsy)HistologyCultureRapid urease testingNoninvasive testingSerological testUrea breath testFecal antigen test

32. Invasive TestingAll of these tests require biopsy to be acquired via endoscopyHistologyMicrobiologic examination using various stainsExcellent sensitivity and specificity but it is invasive, expensive and requires trained personnelCultureCulture of biopsyCostly, time consuming, and technically difficult

33. Invasive TestingRapid Urease TestingRapid urease tests detect the presence of ammonia in the biopsy sample The ammonia is generated by H.pylori urease activityTest of choice at endoscopyGreater than 90% sensitive and specificEasily performed with rapid resultsTests for active HP infection

34. Noninvasive Tests (Antibody Detection/Serological Test)A simple blood testLaboratory-based (more accurate than office-based tests)Office-based Detects IgG antibodies to H. pylori in the serumQuick, noninvasive, inexpensive but has a low positive predictive value in populations where prevalence of HP infection is low.Can’t be used to distinguish between an active infection or past exposure because antibodies persist for long periods of time Most patients remain seropositive for 6 months to 1 year after HP eradicationCan’t be used to determine if eradication is successful

35. Noninvasive Tests (Urea Breath Test)Detects the exhalation of radioactive CO2 following ingestion of 13C or 14C radiolabeled ureaH. pylori hydrolysis of the radiolabeled urea results in radiolabeled CO2 production97% sensitivity and 95% specificity

36. Noninvasive Tests (Fecal Antigen Test)Polyclonal antibody test that detects the presence of H.pylori antigen in the stoolSensitivity and specificity similar to urea breath testPatients may have a reluctance to collect stool samples

37. Noninvasive TestsThe urea breath and fecal antigen tests may be falsely negative in patients who have recently takenAntibiotics (up to 4 weeks)Bismuth compounds (up to 4 weeks)Antisecretory agents (up to 2 weeks)The urea breath and fecal antigen tests can be used as an initial screen to determine if a patient is infected

38. Tests for Confirming EradicationThe urea breath (preferred) and fecal antigen tests can be used to confirm eradiation of H.pylori in a patient who has been treatedThe serological test can not be used to determine eradication because antibodies last for an extended period after the infection has been clearedHowever, confirming eradication is not practical or cost effectiveIndications for confirming eradication include:Continued dyspeptic symptomsH. pylori-associated MALT (mucosal associated lymphoid tissue) lymphomaResection for gastric cancer

39. Testing for H. pyloriLink: Table covering tests for the detection of Helicobacter pylori

40. Treatment/Therapy GoalsChoice of treatment depends on etiology (e.g. HP or NSAIDs) and whether treatment is for initial management or prevention of recurrenceOverall goalsRelief of painHealing of ulcerPrevention of recurrencePrevent or reduce complications

41. Nonpharmacologic TherapyEliminate or reduce psychological stressSmoking cessationEliminate or reduce NSAID useAvoid foods that cause dyspepsia

42. Pharmacologic Therapy OverviewFor an active HP positive ulcer, our goals are to eradicate the HP, heal the ulcer, and ultimately cure the diseaseUse multi-drug regimens containing antibiotics and anti-secretory agents (usually proton pump inhibitors (PPIs)) and sometimes bismuth preparationsFor an NSAID-induced peptic ulcer or a peptic ulcer is not caused by HP, our primary goal is to heal the ulcer as quickly as possibleCan use PPIs, H2-receptor antagonists, or sucralfateAntacids are not used as monotherapy to heal peptic ulcersMisoprostol can be used to reduce the risk of NSAID-induced PUD

43. Proton Pump Inhibitors (PPIs)MOABlocks acid secretion by inhibiting gastric H+/K+ adenosine triphosphatase found on the secretory surface of gastric parietal cellsResults in a long-lasting anti-secretory effect that can maintain gastric pH levels above 4AgentsDexlansoprazole (Dexilant)Esomeprazole (Nexium)Lansoprazole (Prevacid)Omeprazole (Prilosec)Omeprazole/sodium bicarbonate (Zegerid)Pantoprazole (Protonix)Rabeprazole (Aciphex)

44. Proton Pump Inhibitors (PPIs)Common adverse effectsHeadache, dizziness, somnolence, diarrhea, constipation, flatulence, abdominal pain, nauseaSerious adverse effectsIncreased risk of Clostridium difficile infectionsIncrease risk of community-acquired pneumoniaLong-term adverse effects (> 1 year)HypomagnesemiaBone fracturesVitamin B12 deficiency

45. Proton Pump Inhibitors (PPIs)MonitoringAppearance of diarrhea (frequency and type of diarrhea episodes)Periodic magnesium levels (if long-term therapy)Routine bone density studies (DXA scans) If other risk factors for osteoporosis or bone fractures presentPatient counselingPreferable to take a PPI 30 to 60 minutes before a meal (mainly breakfast)If a second dose is needed, take prior to the evening mealOnset of relief is 2 to 3 hours and the duration of relief is 12 to 24 hours

46. Evaluate the Risks versus Benefits of Long-Term PPI UseLong-term PPI use has been associated with increased risk of:FracturesInfections such as C. Diff and pneumonia (expand)HypomagnesemiaVitamin B12 deficiency

47. Evaluate the Risks versus Benefits of Long-Term PPI UseLong-term PPI use MAY BE associated with increased risk of:DementiaRenal diseaseCardiovascular disease

48. H2-Receptor AntagonistsMOACompetitive inhibition of histamine at H2 receptors of gastric parietal cells which inhibits gastric acid secretionAgentsCimetidine (Tagamet)Famotidine (Pepcid)Nizatidine (Axid)Ranitidine (Zantac)

49. H2-Receptor AntagonistsAdverse effectsHeadache, somnolence, fatigue, dizziness, constipation, diarrheaMonitoringMonitor for CNS effects (rare) in those over 50 years old or in those with renal or hepatic impairmentPatient counselingIf taking once a day, it is preferable to take the dose at bedtimeOnset of relief is 30 to 45 minutes and duration of relief is 4 to 10 hours

50. MisoprostolMOAA synthetic prostaglandin E1 analog that replaces the protective prostaglandins that are decreased from prostaglandin inhibiting therapies such as NSAIDsEnhances natural gastromucosal defense mechanisms and healing by increasing the production of gastric mucous and mucosal secretion of bicarbonateInhibits basal and nocturnal acid secretion by direct action on the parietal cellsAgentMisoprostol (Cytotec)Adverse effectsDiarrhea, abdominal pain, headache, nausea/vomiting, flatulence, dysmenorrhea, hypophosphatemia

51. MisoprostolMonitoring Pregnancy testSerum phosphatePatient CounselingPregnancy category XIs a potential abortifacient

52. Bismuth PreparationsMOABismuth exhibits antimicrobial activity against bacterial and viral gastrointestinal pathogensAgentsBismuth subsalicylate (Pepto-Bismol and others)Bismuth subcitrate potassium (bismuth salt in Pylera capsules)Adverse effectsFecal discoloration, tongue discolorationNeurotoxicity (rare)

53. Bismuth PreparationsMonitoringNo specific monitoringPatient counselingMay cause temporary, harmless darkening of the tongue and/or stoolAvoid bismuth subsalicylate if have an aspirin allergy

54. SucralfateMOAThought to form an ulcer-adherent complex at the ulcer site protecting it from further injury from stomach acidAgentSucralfate (Carafate)Adverse EffectsConstipation, bezoar formation, hyperglycemia in diabetes patients, aluminum toxicity in patients with chronic renal failure or on dialysis

55. SucralfateMonitoringBlood glucose in diabetes patientsRenal function in elderly patientsPatient counselingTake on an empty stomachDo not take antacids 30 minutes before or after taking sucralfate

56. AntacidsMOANeutralize hydrochloric acid in the stomach, which results in an increase in gastric pHAgentsMagnesium hydroxideAluminum hydroxideCalcium carbonateAdverse effectsDiarrhea (magnesium hydroxide)Constipation (aluminum hydroxide and calcium carbonate)Alterations in mineral metabolismAcid-base disturbances

57. AntacidsMonitoringPeriodic calcium and phosphate levels if on chronic antacid therapyPatient counselingAntacids can decrease the levels of numerous other drugs including tetracyclines, digoxin, iron supplements, fluroquinolones, and ketoconazole. Patients should separate antacids and other medications by at least 2 hours Patients with renal impairment should not use aluminum or magnesium containing antacids unless directed by their physicianOnset of relief is less than 5 minutes and duration of relief is 20 to 30 minutes Link: Table on Composition and Acid Neutralizing Capacities of Popular Antacid Preparations

58. Drug Used in PUD Therapy RegimensLink: Drug Dosing TableLink: Drug Monitoring Table

59. Treatment of H. pylori-Positive UlcersMulti-drug regimens that include antimicrobials and anti-secretory agents are used to eradicate H. pylori infectionH. pylori has been developing resistance to some antibiotics, particularly clarithromycinFirst-line therapies should have an eradication rate of greater than 80%Regional bacterial resistance patterns need to be taken into account when recommending therapyIf a second course of H. pylori eradication therapy is needed, the second regimen should contain different antibioticsH.pylori eradication regimensTriple TherapyBismuth-based Quadruple TherapySequential TherapySalvage Therapy

60. Triple TherapyStandard triple therapy regimen containsAmoxicillin 1000mg twice day PLUS Clarithromycin 500mg twice a day PLUS a PPI dosed once to twice a dayGiven for 10 to 14 days14 day regimens are generally preferred as 14 day regimens significantly increases the eradication rateIf the patient is allergic to penicillin, then metronidazole 500mg twice a day can be substituted for the amoxicillin

61. Triple TherapyStandard triple therapy is considered first-line in areas where the clarithromycin resistance rate of H. pylori is less than 20%Adding probiotics (specifically Saccharomyces boulardii and Lactobacillus) to triple therapy has been shown to increase eradication rates and decrease adverse effects of treatment, particularly diarrhea

62. Bismuth-based Quadruple TherapyBismuth-based quadruple-therapy containsTetracycline 500mg 4 times day PLUS Metronidazole 250-500mg 4 times a day PLUS Bismuth subsalicylate 525mg 4 times a day PLUS a PPI once or twice a day OR H2-receptor antagonist twice a dayPylera is a brand name product that is a 3 in 1 capsuleEach capsule contains Tetracycline 125mg, Metronidazole 125mg, and Bismuth subcitrate potassium 140mgDose is 3 capsules 4 times a day plus a PPI twice a dayBismuth-based quadruple regimens are given for 10 to 14 days

63. Bismuth-based Quadruple TherapyMay be used as first-line therapy in areas where the clarithromycin resistance rate is ≥ 20%May also be considered for first-line therapy in those with penicillin allergy or in those who have been previously treated with a macrolide antibioticMay also be used if first-line standard triple therapy fails (e.g. as second-line therapy or salvage therapy)

64. Sequential TherapyNewer HP eradication therapy where the antibiotics are administered in a sequence rather than at the same timeSequential therapy contains:A PPI twice a day for 10 days ANDAmoxicillin 1000mg twice day days 1 – 5, followed by Clarithromycin 500mg twice day PLUS Tinidazole 500mg OR Metronidazole 500mg twice a day days 6 – 10. Given for 10 days total (5 days for each antibiotic regimen)

65. Sequential TherapyAdherence and tolerance rates of sequential therapy are similar to triple therapy but the cost is lowerThe American College of Gastroenterology (ACG) Guidelines state that additional validation of sequential therapy needs to occur in North America before it is recommended as a first-line regimen

66. Levofloxacin-Based Triple TherapyLevofloxacin-based Triple Therapy contains:Amoxicillin 1000mg twice a day PLUS Levofloxacin 500mg once a day PLUS a PPI twice a dayGiven for 10 daysThis regimen is an option for salvage therapy in patients who have persistent H. pylori infectionThis therapy regimen needs validation in North America

67. PPI after H. pylori Eradication Therapy CompletionWhen treating an active ulcer, anti-secretory therapy with a PPI is usually continued for 2 weeks after completing the eradication therapy regimenTypically PPI treatment beyond 2 weeks after completion of eradication therapy is not needed for ulcer healing

68. Treatment of NSAID-Induced UlcersIdeally, discontinue the NSAID and treat with standard healing regimens of a PPI, H2-receptor antagonist, or sucralfateLink: Drug Dosing TablePPIs are usually preferred because they provide the fastest symptom relief and ulcer healing

69. Treatment of NSAID-Induced UlcersIf the NSAID needs to be continued:Consider:Reducing the dose of the NSAID ORChange NSAID to one of the followingAcetaminophenA nonacetylated salicylate (salsalate, trisalicylate)A partially selective COX-2 inhibitor (etodalac, nabumetone, meloxicam, diclofenac, celecoxib)Use a PPI to treat the ulcerWhen an NSAID needs to be continued, PPIs are the drugs of choice to treat and heal the ulcer

70. Reducing the Risk of NSAID-Induced Ulcer and GI ComplicationsStrategies to reduce the risk of NSAID-induced ulcersIn GI toxicity high risk patients, use either a PPI or misoprostol as co-therapy along with the NSAIDUse a selective COX-2 inhibitor instead of a nonselective NSAIDWhen selecting a strategy, cardiovascular risk of the patient must also be considered

71. GI and Cardiovascular Safety Issues with NSAIDsThere is no difference in cardiovascular risk between the selective COX-2 inhibitors, the partially selective NSAIDs, and the non-selective NSAIDs with the exception of naproxenWhen compared with all the other NSAIDs, naproxen has the best cardiovascular safety profileLink: Table on Risk Factors Associated with NSAID-Induced Ulcers and Upper GI Complications

72. GI and Cardiovascular Safety Issues with NSAIDsGuidelines for reducing GI risk for patients receiving chronic NSAID therapyLink: Table on Guidelines for Reducing GI Risk for Patients Receiving Chronic NSAID TherapyGuidelines take both CV risk and GI toxicity risk into account when recommending a strategy to reduce the risk of developing a peptic ulcer in those who need chronic NSAID therapy

73. Treatment of Non-H. pylori, Non-NSAID UlcersVery few patients have non-H. pylori, non-NSAID (idiopathic) peptic ulcersIf an idiopathic peptic ulcer is confirmed, treatment with standard ulcer healing therapy should be initiatedStandard H2-receptor antagonist or sucralfate dosage regimens heal the majority of gastric and duodenal ulcers in 6 to 8 weeksStandard PPI dosage regimens heal the majority of gastric and duodenal ulcers in 4 weeksLink: Drug Dosing Table

74. Maintenance Therapy with Anti-Secretory AgentsMaintenance therapy (to maintain ulcer healing, prevent recurrence and complications) with anti-secretory agents like PPIs is only indicated in the following groups of high risk patients:Those who have failed H. pylori eradicationThose who have a history of ulcer related complicationsThose who have frequent recurrences of H. pylori-negative ulcersThose who are heavy smokersThose who NSAID usersStandard maintenance doses as listed in Drug Dosing Table are appropriate for most of these patients

75. Treatment of Gastric Acid Hypersecretion from Zollinger-Ellison Syndrome (ZES)PPIs are the oral drugs of choice for managing gastric acid hypersecretion from ZESTreatment should be started with omeprazole 60mg per day or an equivalent dose of another PPIThis PPI daily dose should be divided and the PPI given every 8 to 12 hours Additional pharmacologic and non-pharmacologic treatments are instituted depending on the gastrinoma itself and any other complications that may be present

76. Treatment of Refractory UlcersUlcers are considered refractory to therapy when symptoms, ulcers, or both persist beyond 8 to 12 weeks despite conventional treatment as previously described or when several courses of H. pylori eradication therapy failPatient should undergo an upper endoscopy to assess the situationTreatment depends on cause and may include additional H. pylori eradication attempts, higher PPI dosages, or surgery

77. Evaluation and Management of PUDLink: Algorithm for the evaluation and management of PUD

78. Additional Patient CounselingDiscuss with the patient the cause of the ulcer (e.g. H. pylori, NSAIDs, etc.)Address risk factors (e.g. NSAID use, cigarette smoking, etc.)Discuss the rationale behind the multi-drug regimens and the importance of adherence and sticking to the full course of therapyCaution patient to look out for signs of GI bleeding (e.g. tarry stools, abdominal pain, vomiting with evidence of blood)

79. ReferencesAtherton JC, Blaser MJ. Helicobacter pylori Infections. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 19e. New York, NY; McGraw-Hill; 2015.Kee Song L, Topazian M. Gastrointestinal Endoscopy. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015.Del Valle J. Peptic Ulcer Disease and Related Disorders. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015.

80. ReferencesLove BL, Thoma MN. Chapter 20. Peptic Ulcer Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014.Wallace JL, Sharkey KA. Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. Martin CP, Talbert RL. Section 5. Gastroenterology. In: Martin CP, Talbert RL. eds. Pharmacotherapy Bedside Guide. New York, NY: McGraw-Hill; 2013.

81. ReferencesChey WD, Wong B, et al. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am J Gastroenterol 2007; 102: 1808-1825.Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59: 1143-1153.Rimbara E, Rischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol 2011; 8: 78-88.Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at anti-Helicobacter pylori therapy. World J Gastroenterol 2011; 17: 3971-3975.

82. ReferencesMicromedex Solutions.  Truven Health Analytics, Inc. Ann Arbor, MI.  Accessed November 1, 2016.Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc. Accessed November 1, 2016.