Peptic Ulcer Disease

1. A.Mayet. Pharm.D, BCPS, BCNSP Associate Professor K S U Peptic Ulcer Disease

2. GERD • A condition which develops when reflux of stomach contents causes troublesome symptoms and/or complications.

3. Syndromes with esophageal injury • (a) Reflux esophagitis • (b) Reflux stricture • (c) Barrett esophagus • (d) Adenocarcinoma

4. Extraesophageal syndromes • i. Established association • (a) Reflux cough • (b) Reflux laryngitis • (c) Reflux asthma • (d) Reflux dental erosions

5. Proposed association • (a) Sinusitis • (b) Pulmonary fibrosis • (c) Pharyngitis • (d) Recurrent otitis media

6. Typical symptoms: Heartburn (pyrosis), regurgitation, acidic taste in the mouth

7. Extraesophageal symptoms : Chronic cough, asthma-like symptoms, recurrent sore throat, laryngitis/hoarseness, dental enamel loss, and noncardiac chest pain; sinusitis/ pneumonia/ bronchitis/otitis media are less common atypical symptoms.

8. Alarm symptoms: Dysphagia , odynophagia, bleeding, weight loss, choking, chest pain, and epigastric mass. • These symptoms warrant immediate referral for more invasive testing.

9. Aggravating factors: Recumbency (gravity), increased intra-abdominal pressure, reduced gastric motility, decreased lower esophageal sphincter (LES) tone, and direct mucosal irritation

10. Long-term complications: Esophageal erosion, strictures/obstruction, Barrett esophagus, and reduction in patient’s quality of life

11. Diagnosis (symptoms) • Patient description of classic GERD symptoms, such as pyrosis, is often enough to consider it an initial diagnosis; invasive testing is therefore not indicated in uncomplicated cases. • The AGA guidelines state that it is reasonable to assume a diagnosis of GERD in patients who respond to initial acid-suppressive therapy, particularly proton pump inhibitors (PPIs).

12. Diagnosis • Symptoms do not predict the degree of esophagitis or complications secondary to GERD, if present. • Patients presenting with extraesophageal symptoms should be assessed on a case-by-case basis to consider the need for referral or alternative/invasive testing. • Cardiac etiologies (ischemic) should be considered and explored before arriving at a diagnosis of reflux chest pain syndrome.

13. Diagnosis (endoscopy) • Considered the technique of choice to identify Barrett esophagus (with biopsy) or complications of GERD • Findings of typical symptoms in association with endoscopic mucosal changes are about 97% specific for the diagnosis of GERD

14. Most patients with typical/atypical symptoms will have normal-appearing esophageal mucosa on endoscopy • Biopsies should be performed in areas of suspected metaplasia, dysplasia, or malignancy • Routine endoscopy to assess disease progression is not recommended

15. Manometry • Used to evaluate peristaltic function of the esophagus in patients with normal endoscopic findings • Should be used before pH testing to rule out esophageal motility disorders and to help localize the LES for subsequent pH testing (grade B)

16. pH Testing • The main outcome measure of esophageal pH monitoring is the percentage of time the pH value is less than 4 in a 24-hour period.

17. pH Testing • Ambulatory pH testing is useful in the following clinical situations: • Patients with no mucosal changes on endoscopy and normal manometry who have continued symptoms (both typical and atypical) (grade B) • Patients who are refractory to therapeutic doses of appropriate pharmacologic agents • Monitoring of reflux control in patients with continued symptoms on drug therapy

18. pH Testing • Sensitivity/specificity of 96% reported • The PPIs should be withheld for 7 days before pH testing, if possible, for the most accurate results.

19. GERD and H Pylori • Role of H. pylori testing and eradication is controversial in patients presenting with GERD • Symptoms should be assessed on the basis of patient presentation and risk factors for gastric cancer.

20. Treatment Strategies for GERD • A 4-week trial of a twice-daily PPI can be considered for patients thought to have reflux chest pain syndrome before manometry or pH testing (grade A). • Rule-out ACS (troponin, ECG) • Sensitivity and specificity of a short course of PPIs are 80% and 74% for diagnosing reflux chest pain syndrome.

21. Treatment Strategies for GERD • Nonpharmacologic interventions/lifestyle modifications are unlikely to control symptoms in most patients. • The AGA guidelines cite insufficient evidence to advocate lifestyle modifications for all patients, but rather, they advocate use in targeted populations.

22. Treatment Strategies for GERD • Avoid aggravating foods/beverages; some may reduce LES pressure (alcohol, caffeine, chocolate, citrus juices, garlic, onions, peppermint/spearmint) or cause direct irritation (spicy foods, tomato juice, coffee). • Reduce fat intake (high-fat meals slow gastric emptying) and portion size. • Avoid eating 2–3 hours before bedtime. • Remain upright after meals.

23. Treatment Strategies for GERD • Weight loss for overweight or obese patients (grade B) • Reduce/discontinue nicotine use in patients who use tobacco products (affects LES). • Elevate the head of the bed (6–8 in.) if reflux is associated with recumbency (grade B). • Avoid tight-fitting clothing (decreases intra-abdominal pressure).

24. Treatment Strategies for GERD • Avoid medications that may reduce LES pressure, delay gastric emptying, or cause direct irritation: α-Adrenergic antagonists, anticholinergics, benzodiazepines, calcium channel blockers, estrogen, nitrates, opiates, tricyclic antidepressants, theophylline, NSAIDs, and aspirin.

25. Pharmacologic Therapies • “Step-down” treatment: Starting with maximal therapy, such as therapeutic doses of PPIs, is always appropriate as a first-line strategy in patients with documented esophageal erosion. • Advantages: Rapid symptom relief, avoidance of over-investigation • Disadvantages: Potential overtreatment, higher drug cost, increased potential of adverse effects

26. Pharmacologic Therapies • “Step-up” treatment: Starting with lower-dose OTC products. • Advantages: Avoids overtreatment, has lower initial drug cost. • Disadvantages: Potential under treatment (partial symptom relief), may take longer for symptom control, may lead to over investigation

27. AGA guideline recommendations • Empiric drug therapy is appropriate for patients with uncomplicated heartburn. • Use of antisecretory drugs for patients with esophageal GERD symptoms, with or without esophagitis, is strongly recommended (grade A). • PPIs are more effective than histamine2-receptor antagonists (H2RAs), which are, in turn, better than placebo for patients with esophageal GERD symptoms.

28. Pharmacologic Therapies • All PPIs are similar in efficacy when used for patients with esophageal GERD symptoms. • Data are weak to support using PPIs or H2RAs above standard doses. However, twice-daily dosing of PPIs is appropriate in patients who continue to have symptoms on once-daily PPI therapy (grade B).

29. Pharmacologic Therapies • Rapid-acting drugs should be used for patients who wish to take the drug in response to symptoms • Antacids are the fastest-acting agents available and may be combined with both PPIs and H2RAs.

30. Pharmacologic Therapies • Maintenance therapy is appropriate for patients with esophagitis in whom PPIs have been effective (grade A). • Titration to the lowest effective dose is recommended.

31. Pharmacologic Therapies • Most patients with nonerosive disease will continue on maintenance therapy if they initially respond, but it may not be possible to titrate them down to on-demand therapy. • On-demand therapy is not appropriate for patients with erosive esophagitis.

32. Pharmacologic Therapies • Dosing PPIs less than once daily as maintenance therapy is ineffective for patients who initially had erosive esophagitis • No evidence of improved efficacy by adding a bedtime dose of H2RA to twice-daily PPI therapy

33. Pharmacologic Therapies • AGA guideline recommendations for the management of extraesophagealsymptoms • Chronic cough, laryngitis, and asthma all have definite associations with GERD.

34. Pharmacologic Therapies • Evidence is fair (grade B) for the use of once- or twice-daily PPI therapy in patients with an extraesophageal syndrome and a concomitant esophageal GERD syndrome (grade B). • A 2-month trial of twice-daily PPI therapy would be an appropriate therapy for these patients.

35. Pharmacologic agents • Antacids • Calcium-, aluminum-, and magnesium-based products are available OTC in a wide variety of formulations • Neutralizing acid and raising intragastric pH results in decreased activation of pepsinogen and increased LES pressure; rapid onset of action but short duration, necessitating frequent dosing

36. Pharmacologic Agents • Used as first-line therapy for intermittent (less than 2 times/week) symptoms or as breakthrough therapy for those on PPI/H2RA therapy; not appropriate for healing established esophageal erosions

37. Adverse reactions • Constipation (aluminum), diarrhea (magnesium), accumulation of aluminum/magnesium in renal disease with repeated dosing • Drug interactions: Chelation (fluoroquinolones, tetracyclines), reduced absorption because of increases in pH (ketoconazole, itraconazole, iron, atazanavir, delavirdine, indinavir, nelfinavir) or increases in absorption leading to potential toxicity (raltegravir, saquinavir)

38. Histamine2-receptor antagonists • Reversibly inhibit histamine2-receptors on the parietal cell • All agents available as prescription and OTC products; a variety of formulations available; generics exist for all prescription products

40. Therapy with H2RAs is less efficacious than therapy with PPIs in healing erosive esophagitis

41. Adverse effects • Most are well tolerated. Central nervous system (CNS) effects, such as headache, dizziness, fatigue, somnolence, and confusion, are the most common. • Elderly patients and those with reduced renal function are more at risk. • Prolonged cimetidine use is associated with rare development of gynecomastia.

42. Drug interactions • May affect absorption of drugs dependent on lower gastric pH, such as ketoconazole, itraconazole, iron, atazanavir, delavirdine, indinavir, and nelfinavir, or increases in absorption leading to potential toxicity (raltegravir, saquinavir).

43. Drug interactions • Cimetidine also inhibits cytochrome P450 (CYP) enzymes 1A2, 2C9, 2D6, and 3A4. Warfarin, theophylline, and other agents metabolized by these enzymes may be affected. • Cimetidine may also compete with medications and creatinine for tubular secretion in the kidney.

44. Proton pump inhibitors • Irreversibly inhibit the final step in gastric acid secretion; greater degree of acid suppression achieved and typically longer duration of action than H2RAs • Most effective agents for short- and long-term management of GERD, as well as for management of erosive disease • Pantoprazole, lansoprazole, and esomeprazole are available in intravenous formulations.

45. Proton pump inhibitors

48. Adverse reactions • Overall, well tolerated; possible adverse effects include headache, dizziness, nausea, diarrhea, and constipation. Long-term use is not associated with significant increases in endocrine neoplasia or symptomatic vitamin B12 deficiency

49. Proton pump inhibitors • Both PPIs and H2RAs found an elevated risk of community-acquired pneumonia with these agents. • The adjusted relative risk of pneumonia was 1.89 (95% confidence interval [CI], 1.36–2.62) with PPI use and 1.63 (95% CI, 1.07–2.48) for H2RA use

50. Proton pump inhibitors • A recent large prospective cohort study of hospitalized patients revealed an increased risk of hospital-acquired pneumonia in nonventilated patients who were prescribed PPIs (OR = 1.3; 95% CI, 1.1–1.4) (JAMA 2009;301:2120–8).