Peptic ulcer

Current Trends in Ulcer Management.
Pathophysiology of Ulcer. Pharmacological and non-pharmacological treatments etc.

1. CURRENT TRENDS IN THE MANAGEMENT OF PEPTIC ULCER DISEASE (PUD) De-Graft Gyamfi Adjei 1

2. OUTLINE INTRODUCTION DEFINITION HISTORY EPIDEMIOLOGY ETIOLOGY ANATOMY PATHOPHISIOLOGY CLINICAL PRESENTATIONS INVESTIGATIONS MANAGEMENT ACKNOWLEDGENT REFERENCES 2

3. INTRODUCTION Peptic ulcer refers to a break in the lining of the stomach, first part of the small intestine or occasionally the lower oesophagus . 3

4. CLASIFICATION OF PEPTIC ULCER DISEASE The major forms of PUD are: Gastric Ulcer Duodenal Ulcer Gastric Ulcer: ulcers that occur in the stomach Duodenal Ulcer: ulcers that occur in the upper area of the small intestine 4

5. SYMPTOMS OF DUODENAL ULCERS Localized pain(pin point), restricted to mid- epigastrum Nocturnal pain Relieved by food and antacids Pain may radiate to costal margins of the back or the right shoulder Weight gain (probably due to ↑ urge to eat to relieve pain) 5

6. SYMPTOMS OF GASTRIC ULCERS Pain is more diffuse – over a wide area of mid epigastric region Rarely produces nocturnal pain Pain precipitated by food Pain may be referred to the left subcostal region Weight loss common with GU 6

7. HISTORY EARLY 20 TH CENTURY: Ulcers were believed to be caused by stress an dietary factors. Later gastric acid was blamed for peptic ulcer disease 7

8. …HISTORY 1982 first identified the link between Helicobacter pylori and ulcers. 1994 NIHCDC concluded that there Is a strong link between H. pylori and ulcer dxs Pxs be treated with antibiotics 8

9. …HISTORY 1996 The FDA approves the first antibiotic for treatment of ulcer disease 1997 The CDC launches campaign to inform healthcare providers and consumers about the link between H. pylori and ulcers 9

10. EPIDEMIOLOGY In the US, PUD affects 4.5million people annually Approximately 10% of the US population has evidence of duodenal ulcer at some time, Of those infected with H. pylori, the lifetime prevalence is approx. 20% Only about 10% of young persons have H. pylori infection 10

11. EPIDEMIOLOGY Overall, the incidence of Duodenal ulcer has been decreasing over the past 3-4 decades The prevalence of PUD has shifted from predominance in males to similar occurences in males and females In May 2014, WHO established that in Ghana, the death rate due to PUD was 9.55 per 100,000 persons 11

12. EPIDEMIOLOGY(KBTH) Patience attendance at OPD 2013- 13744 persons 2014- 13051 persons Out of the above population, PUD cases were 587(4.2%) in 2013 and 1177(9.01%) in 2014 Females represented 55-58% of the population recorded <5% had surgery 12

13. EPIDEMIOLOGY(KBTH) At the endoscopy unit, 1144(36.0%) were confirmed to have PUD in 2013 PUD was ranked one of the top 10 causes of admission for three consecutive years PUD was ranked the 9 th major cause of admission(in males) and 10 th in females at the polyclinic 13

14. EPIDEMIOLOGY 14

15. ETIOLOGY The 2 most common risk factors for PUD are: Helicobacter pylori Non steroidal anti- inflammatory drugs Other uncommon risk factors include: Lifestyle factors( e.g ageing, smoking, alcohol intake) Severe physiologic stress Hypersecretory states Genetic factors 15

16. ETIOLOGY- Helicobacter pylori 16

17. Helicobacter pylori H. pylori is a Gram-negative, spiral & microaerophyllic bacterium with multiple flagella at one end Adheres to gastric epithelial lining. Produces various enzymes - urease, haemolysins, fusidase , neuraminidase. About 2/3 of world population infected , with an estimated prevalence of 80-90 % in the developing world 17

18. Helicobacter pylori Infected persons have up to 6-fold increased risk of developing gastric cancers Most likely spread from person to person through faecal-oral and oral-oral routes. 18

19. Pathogenesis of H. pylori infection The Flagella make it motile, allowing it to live deep beneath the mucus layer It uses an adhesin molecule to bind to epithelial cells Where the pH there is close to neutral 19

20. 2 . Etiology -Non-Steroidal Anti-inflammatory Drugs (NSAIDS) Symptomatic GI ulceration occurs in 2% - 4% of patients treated with NSAIDs for 1 year The effects of aspirin & NSAIDs on the gastric mucosa ranges from mucosal hemorrhages to erosions & acute ulcers 20

21. NSAIDS Inhibit the production of prostaglandins resulting in: 1. Decrease mucus & HCO3 production 2. Decrease mucosal blood flow 3. Reduce cell renewal HCl aggravates NSAID-induced mucosal injuries by Converting superficial injury to deeper mucosal necrosis, Interfering with haemostasis & platelet aggregation Impairing ulcer healing 21

22. Types of NSAID & Risk of Ulcer 22 Risk Group Drug Low Ibuprofen Medium Naproxen Diclofenac Indomethacin High Piroxicam,Ketoprofen Azapropazone

23. PATHOPHYSIOLOGY The upper G.I system consists of Oesophagus Stomach Duodenum Stomach Cardia : secretion of mucous Body: parietal cells Chief cells Antrum : G cells D cells 23

24. PATHOPHYSIOLOGY Gastric Secretions ( About 2.5L HCL daily) smooth muscle – churning sub-mucosa – veins and arteries that carries blood to the liver 24

25. PATHPHYSIOLOGY The gastroduodenal mucosal integrity is determined by adequate balance between protective(defensive) and damaging(aggressive) factors When the aggressive factors increase or the defensive factors decrease, mucosal damage will result leading to ulcerations 25

26. PATHOPHYSIOLOGY DEFENSIVE FACTORS Bicarbonate Mucus layer Mucosal blood flow Prostaglandins Rapid epithelial renewal AGGRESSIVE FACTORS Helicobacter pylori HCl NSAIDs Stress Smoking& alcohol Ageing 26

27. PATHOPHYSIOLOGY 27

28. PATHOPHYSIOLOGY Two major variants in peptic ulcers are commonly encountered in the clinical practice: Duodenal Ulcer (DU) Gastric Ulcer (GU) DU: increased acid load to the duodenum due to: Increased parietal cell mass Increased gastrin secretion (e.g. Zollinger -Ellison syndrome, alcohol & spicy food) H. pylori damaging somatostatin-producing cells Increased gastric emptying rate HCO3 secretion is decreased in the duodenum by H. pylori inflammation Increased vagal nerve stimulation 28

29. PATHOPHYSIOLOGY GU results from the break down of gastric mucosa : The local epithelial damage due to cytokines released by H. pylori Pyloric sphincter dysfunction or obstruction Reflux of bile salts into the stomach Nicotine- delaying ulcer healing 29

30. Pathogenesis of H. pylori infection Effects of H. pylori on gastric Hormones 30 - ↓ Somatostatin production from antral D-cells due to antral gastritis Low somatostatin will ↑ Gastrin release from G-cell  hypergastrinemia This will stimulate acid production by the parietal cells  leading to further duodenal ulceration. This effect is exaggerated among smokers!

31. DIAGNOSIS Involves 3 Criteria Patient history taking Risk Factors Symptoms Clinical Signs epigastric tenderness GI bleeding Investigations Endoscopy for ulcer detection H. pylori Detection 31

32. DIAGNOSIS OF H. pylori Non-invasive C 13 or C 14 Urea Breath Test Stool antigen test H. pylori IgG titer (serology) Invasive Gastric mucosal biopsy with histology Rapid Urease test (CLO test) 32

33. DIAGNOSIS OF H. pylori Non-invasive 1. C13 or C14 Urea Breath Test 33 The best test for the detection of an active infection

34. DIAGNOSIS Non-invasive Serology for H pylori Serum Antibodies ( IgG ) to H pylori (Not for active infection) Fecal antigen testing (Test for active HP). Invasive Upper GI endoscopy Highly sensitive test Patient needs sedation 34

35. Endoscopy (Invasive) Detects the site and the size of the ulcer, even small and superficial ulcer can be detected Detect source of bleeding Biopsies can be taken for rapid urease test , histopathology & culture 35

36. Invasive ( endoscopy) Rapid urease test ( RUT) Considered the endoscopic diagnostic test of choice Gastric biopsy specimens are placed in the rapid urease test kit. If H pylori are present, bacterial urease converts urea to ammonia, which changes pH and produces a COLOR change 36

37. Duodenal Ulcer on Endoscopy 37 Normal duodenal bulb Duodenal Ulcer

38. Gastric Ulcer on Endoscopy 38 Chronic Gastric Ulcers

39. DU/GU ON ENDOSCOPY 39

40. PUD COMPLICATIONS GI bleeding Perforation Gastric /duodenal obstruction(presents with projectile vomiting, pyloric stenosis ) Haemorrhage –may lead to Chronic anemia Recurrence Malignancy- gastric ulcers 40 Bleeding DU Perforated GU Duodenal stricture

41. PUD COMPLICATIONS 41 OBSTRUCTION – PYLORIC STENOSIS

42. PUD and CANCER Vacuolating cytotoxins ( vac A) Pore-forming proteins Permeability Suppresses immunity Cytotoxin associated gene (cag A) Oncogenic proteins Changes morphology Apoptosis 42

43. INTERVENTIONS Surgical interventions may be required in certain cases Malignant ulcers Pyloric stenosis Chronic ulcerations Uncontrolled bleeding perforations 3 main surgical procedures Vagotomy Antrectomy Pyloroplasty 43

44. MANAGEMENT OF PEPTIC ULCER DISEASE 44

45. NON PHARMACOLOGICAL TREATMENT Avoid smoking/smoke cessation Avoid foods that aggravate the pain Allay anxiety and stress; reduced if possible Regular small meals Moderation of coffee and tea Avoid late night snacks as they stimulate nocturnal gastric acid secretion Avoid alcohol Have enough rest Avoid NSAID’s when necessary 45

46. GOALS OF TREATMENT Pharmacological treatment To relieve pain and reduce gastric acid secretions To promote healing of the ulcer To eradicate H. pylori if present To prevent recurrence of ulcer To avoid complications 46

47. PEPTIC ULCER DRUGS Proton pump inhibitors (PPI) H 2 – receptor antagonist Prostaglandin analogues Sucralfate Antacids BISMUTH CHELATES(no longer used ; neurotoxic) Selective anti- muscaranics ( Pirenzepine ) 47

48. PROTON PUMP INHIBITORS- PPI’s PPI’s are weak bases and hence need enteric coating to protect it from the acidic state of the stomach PPI’s bind irreversibly to the proton pump, hence have more sustained duration of acid inhibition Should be taken 30minutes before meals PPI’s should not be given before an endoscopy as they may mask serious underlying pathology 48

49. EXAMPLES OF PPI’S Omeprazole/ Esomeprazole Lansoprazole Pantoprazole 49

50. PPI’s contd Mechanism of action: Inhibits the production of gastric acid by blocking the hydrogen-potassium adenosine triphosphate enzyme system ( h+k += atpase ) of gastric parietal cells in the gastric mucosa Thus the exchange of hydrogen and potassium across the membrane to maintain gastric acidity is inhibited 50

51. PPI’s Adverse effects: Usually mild and reversible Diarrheoa Headache Nausea Abdominal pain Constipation and dizziness Prolonged use of PPI’s is associated with hypomagnesemia 51

52. Pharmacokinetics of PPI’s Characteristic Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole Bioavailability(%) 30-40 80-85 52 77 64-89 Time to peak [plasma] (hrs) 0.5-3.5 1.7 2.0-5.0 1.1-3.1 1-2 Plasma elimination t 1/2 (hrs) 0.5-1 1.3-1.7 1.0-2.0 1.0-1.9 1.3 Protein binding(%) 95 97 96 98 97 Urinary excretion of oral dose(%) 77 14-23 30-35 71-80 80

53. H2 RECEPTOR ANTAGONIST- H2RA’s Mechanism of action By blocking histamine type two receptors in gastric parietal cells Thus, preventing acid secretion to reduce gastric output H2 receptor antagonists in combination with PPI at bedtime may enhance gastric PH control at night 53

54. EXAMPLES OF H2RA’s Ranitidine Cimetidine Fomatidine Nizadine 54

55. H2RA’s Effectively heal ulcers when NSAID therapy is stopped main role of H2RA is the empirical management of dyspepsia symptoms 55

56. ADVERSE EFECTS OF H2RA’s Diarrhea Headache Dizziness Rash Tiredness Gynaecomastia and impotence occur occasionally with cimetidine 56

57. Comparison of H2-receptor antagonists. Variable Cimetidine. Ranitidine. Nizatidine. Famotidine. Brand name Tagamet Zantac Axid Pepcid Rel. potency 1 4-10 4-10 20-50 Dose to heal DU(mg) 300 qid 400 bd 800 nocte 150 bd 300 nocte 150 bd 300 nocte 40 nocte Maintenance dose (mg) 400 nocte 150 nocte 150 nocte 20 nocte Dose to heal GU (mg) 300 qid 400 bd 800 nocte 150 bd N/A N/A ABSORPTION Bioavailability (%) 30-80 (60) 30-88 (50) 75-100 (98) 37-45 (43) Time to peak [serum] ( hr ) 1-2 1-3 1-3 1-3.5 VOD (L/kg b.w ) 0.8-1.2 1.2-1.9 1.2-1.6 1.1-1.4

58. PROSTAGLANDIN ANALOGUES Mechanism of action: Has antisecretory and protective properties promoting peptic ulcer healing Can be used as prophylaxis against NSAID induced ulcers Example: Misoprostol ( Cytotec ) 58

59. SIDE EFFECTS Diarrhea (it may be severe and require withdrawal) Nausea &vomiting Dyspepsia Abnormal vagina bleeding with menorrhagia Flatulence Abortifaecient 59

60. SUCRALFATE Aluminium salt of sucrose octasulphate Weak antacid Has mucosal protective effects by stimulating bicarbonates and mucos secretion and stimulation of mucosal prostanoids Effective in the treatment of NSAID induced ulcers if NSAID’s are stopped(2g daily) Main side effect is constipation 60

61. ANTACIDS Acts by neutralizing gastric acid However only effective for a short period Alginates are added to antacids to relieve reflux symptoms Antacids are best given when symptoms occur or are expected 61

62. ANTACIDS Side effects of antacid are considered in choosing type of antacid Aluminium salt antacids may cause constipation While magnesium salts may cause diarrhea Hence a combination of these are preferred to produce neutral effect on intestinal transit Calcium containing antacid may have an effect of rebound acid secretion as calcium stimulates acid secretion Also regular intake may cause hypercalcemia 62

63. ANTACIDS Antacids containing sodium bicarbonates should not be given to patients on restricted salt diet Magnesium trisilicate has very high sodium bicarbonate content Liquid antacids are usually preferred over tablets Antacid Dosing: 10-15mL 8 or 6 hourly; of liquid Mg-Al antacids promote ulcer healing, but less than antisecretary drugs 63

64. ADVERSE EFFECTS OF ANTACIDS Constipation ( Aluminium ) Diarrhoea (Magnesium) Flatulence(Carbonates & bicarbonates) Nausea & vomiting 64

65. EXAMPLES OF ANTACIDS Magnesium sulfate Aluminium salts Calcium carbonate Sodium bicarbonate 65

66. Neutralizing capacity of some commonly used antacid atacid Active components Neutralising capacity ( mEq ) Ducon Al(oh)3 Mg(oh)2 caco3 7.04 Maalox Al(oh)3 Mg(oh)2 2.58 Maalox plus Al(oh)3 Mg(oh)2 simethicone 2.30 Nugel AL(OH)3 Mg(OH)2 MAGNESIUM TRISILLICATE ALGINATE SIMETHICONE aludrox Al(oh)3 Mg(oh)2 2.81 66

67. Management- H. pylori eradication Most patients with DU are infected with H. pylori Eradicate with 7 day course of PPI plus combination of antibiotics classes of antibiotics used include: Macrolide (clarithromycin) Penicillin( amoxycillin ) Metronidazole For initial therapy against H. pylori a 7-10 day triple therapy comprising of a PPI or H2ra, Clarithromycin, and either amoxicillin or metronidazole For a quadruple therapy, bismuth chelate is added. These regimen eradicate h. pylori 85% of cases Dual therapy of PPI and one antibiotic can be used, but produces low rates of eradication PPI regimen is continued for 4-8 weeks to ensure wound healing 67

68. Amoxycillin Active against H. pylori Shown to be 90% active against H. pylori Should not be given to patients with true penicillin allergy Erythematous rash Maculopapular rash GI adverse effects do not constitute allergy (nausea, vomiting, diarrhoea ) Uticarial rash does not constitue true penicillin allergy 68

69. Clarithromycin Very active against h. pylori Generally well tolerated May cause GI adverse effects such as: Nausea Diarrhoea Vomiting Not given to pregnant and lactating women, excreted in milk 69

70. Metronidazole Active against gram negative bacteria including h. pylori Causes disulfiram -like reactions with alcohol Side effect: Metallic taste in mouth GI irritations including nausea and vomiting Metronidazole is not the first line antibiotic in h. pylori eradication But it can be given when there’s treatment failure, symptoms do not resolve. Tinidazole can be give in place of Metronidazole. 70

71. Current trends in management Of peptic ulcer disease 71

72. Overview of treatment Give initial treatment Test for H. pylori Endoscopy and H.pylori retesting Stop NSAID use if possible Ongoing care if symptoms recur or continues 72 NICE guidelines (2015)

73. Initial treatment Offer H. pylori eradication therapy to people who have tested positive for H. pylori and who have peptic ulcer disease. For people using NSAIDs with diagnosed peptic ulcer, stop the use of NSAIDs where possible. Offer full-dose PPI or H2RA therapy for 8 weeks and, if H. pylori is present, subsequently offer eradication therapy. Offer full dose PPI or H2ra for4-8 weeks for people who have tested negative for H. pylori and are not on NSAID’s 73

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75. ENDOSCOPY & H. PYLORI RETESTING Repeat endoscopy and H. pylori retesting for patient 6-8 weeks after treatment This depends on the size of the lesion Carbon 14 breath test may be insufficient at this stage 75

76. NSAID USE Discuss potential of nsaid treatment for people who have to take NSAID’s after the ulcer is healed Review the need for NSAID use regularly, at least every 6 months Consider dose reduction or substituting with paracetamol Or use an alternative or low dose ibuprofen If NSAID continuation is very necessary, consider cox 2 selective NSAIDs 76

77. UHEALED ULCER/ CONTINUED SYMPTOMS/ RECURRENCE In people with an unhealed ulcer, rule out non-adherence, malignancy, failure to detect H. pylori , inadvertent NSAID use or other ulcer-inducing medication and rare causes such as Zollinger –Ellison syndrome or Crohn's disease. If symptoms recur after initial treatment, offer a PPI to be taken at the lowest dose possible to control symptoms. Discuss using the treatment on an 'as-needed' basis with people to manage their own symptoms. 77

78. Current drug regimen- H. pylori eradication PPI ANTIBIOTIC amoxicillin clarithromycin metronidazole Esomeprazole 20mg 12hrly 1g 12hrly 500mg 12hrly ------------ ----------- 500mg 12hrly 400mg 12hrly Omeprazole 20mg 12hrly 1g 12hrly 500mg 12hrly ------------ 500mg 8hrly -------------- 400mg 8hrly -------- 500mg 12hrly 400mg 12hrly Rabeprazole 20mg 12hrly 1g 12hrly 500mg 12hrly --------- ----------- 500mg 12hrly 400mg 12hrly 78

79. CURRENT DRUG REGIMEN- NSAID INDUCED ULCERS Esomeprazole, oral: Adults:-20 mg daily for 4 weeks. Repeat course if ulcer is not fully healed. Or Omeprazole, oral, Adults:20 mg daily for 4 weeks. Repeat course if ulcer is not fully healed. Or Rabeprazole , oral, Adults:20 mg daily for 4 weeks. Repeat course if ulcer is not fully healed. 79

80. CURRENT DRUG REGIMEN- BLEEDING PEPTIC ULCER · Esomeprazole, IV, Adults:40 mg daily Or Omeprazole, IV, Adults:40 mg 12 hourly for up to 5 days 80

81. PATIENT EDUCATION Seek pharmacist advice when purchasing OTC analgesics Patients with risk of peptic ulceration should be advised to avoid otc aspirin and NSAIDs Taking aspirin and NSAIDs with or after food may decrease risk of dyspepsia Patient should be aware of optimum time for administration of PPI, dose duration therapy Misoprostol should not be used in pregnant women and women of child bearing age Patients need to know the importance of adherence to eradication therapy for successful treatment, to prevent resistance 81

82. ROLE OF THE PHARMACIST … Pharmaceutical care for peptic ulcer patients Monitoring treatment Efficacy of treatment: (the signs and symptoms and investigations are looked) the toxicity of the medicines: (relies on harmful side effects). Counselling if patients are adequately counselled on their disease, aims of therapy, life style modification and advice on managing side effects effective concordance can be obtained. 82

83. ROLE OF THE PHARMACIST General public (patient) Education and Counseling on; Potentially harmful agents, including: NSAIDs Aspirin Alcohol Tobacco Caffeine Stress Reduction 83

84. CONCLUSION An understanding of how peptic ulcer occurs, in concept with a good knowledge of potent acid suppressing drugs as well as the implication of H. pylori in PUDs have changed the face of ulcer therapy providing hope for better prognosis over time. 84

85. REFERENCES Annual Report,2013, Korle Bu Teaching Hospital, pp 22,111-112 British National Formulary (BNF) 68 th edition Hatakeyama , M et al (2014). H.pylori cagA and gastric cancer: a paradigm for hit and run carcinogenesis Etc …… 85

86. THANK YOU 86