Pharmacotherapeutics on peptic ulcer disease

1. PEPTIC ULCER DISEASE
Presented by,
Dr. Kavya HB (Pharm D)
Lecturer

2. CONTENTS
 Definition
 Epidemiology
 Etiology
 Pathophysiology
 Clinical manifestations
 Complications
 Diagnosis
 Treatment
- Management
- Non pharmacological
- Pharmacological

3. Definition
• PUD is one of the most common gastroenterologic disease affecting
the upper GI tract.
• An ‘ulcer’ is defined as disruption of the mucosal integrity of the
stomach or duodenum leading to a local defect due to active
inflammation.
• The term ‘peptic ulcer’ describes a condition in which there is a
discontinuity in the entire thickness of the gastric or duodenal
mucosa that persists as a result of acid and pepsin in the gastric
juice.

4. (Or)
• A peptic ulcer is an abnormal area of mucosa that has been damaged
by the pepsin and hydrochloric acid of gastric juice, with consequent
inflammation of the underlying and surrounding tissue.

5. Types of inducer in peptic ulcer:
 H. pylori Induced peptic ulcer
 NSAID Induced peptic ulcer
 Stress related mucosal damage ulcer
Types of peptic ulcer depending on sites:
 Gastric ulcers: which appear in the stomach lining.
 Esophageal ulcers: which appear in the long tube like structure that
connects the stomach with the mouth.
 Duodenal ulcers: which appear in a section of the small intestine
known as the duodenum.

6. Epidemiology
 Acid peptic disorders are very common in the United States, with 4
million individuals (new cases and recurrences) affected per year.
 The prevalence of H. pylori is more common in developing
countries than in industrialized countries H. pylori prevalence
exceeds 80% in adults.
 The prevalence of H. pylori in the United States is 30% to 40%, but
remains higher in ethnic groups such as African and Latin
Americans.

7. Etiology
 Previous peptic ulcer.
 Dyspepsia (Indigestion )
 H. pylori (80–85% of gastric ulcers are associated with H. pylori)
 NSAIDs induced.
 Concomitant use of anticoagulant (warfarin).
 Concomitant use of Antiplatelet drug such as Clopidogrel.
 Concomitant use of oral Bisphosphonates.
 Concomitant use of Selective Serotonin Reuptake Inhibitor (Citalopram).
 Corticosteroids

8.  Cigarette smoking
 Alcohol consumption
 Hypersecretion of acid which occurs in the rare Gastrinoma
(Zollinger–Ellison) syndrome.
 Gastric acid hypersecretion and severe ulcer disease.
 Viral infections (e.g., cytomegalovirus)
 Radiation
 Chemotherapy
 Psychologic stress (feeling of strain and pressure)
 Emotional stress; head injury, spinal cord injury, burns, multiple
trauma.

10. Risk factors:
 Crowded living conditions, unclean water.
 Consumption of raw vegetables.
 Coffee, tea, cola beverages, beer, milk, and spices may cause
dyspepsia, but do not increase the risk for PUD.

11. Pathophysiology

12. H. Pylori induce peptic ulcer disease

13. NSAID’s induced peptic ulcer:

14. Stress induced peptic ulcer:
Circulatory disturbances of the gastro-intestinal blood supply with
necrosis of the apical mucosal cells
Increased gastric acidity (increased histamine release, vagal stimulation
and increased production of glucocorticoids)
Changes in the mucosal barrier (e.g. gastro-duodenal reflux)

15. Cigarette smoking induced peptic ulcer:
Cigarette smoking potentiated ethanol-induced gastric mucosal
damage
The reduction of mucus secretion, increase in Leukotriene B4 level
Increased activities of inducible Nitric oxide synthase, Xanthine oxidase
and Myeloperoxidase
Adhesion molecules in the gastric mucosa
Potentiating effects.

16. Zollinger-Ellison syndrome (ZES)
Caused by a non–beta islet cell
Gastrin-secreting tumor of the pancreas that stimulates the acid-
secreting cells of the stomach to maximal activity
Leads gastrointestinal mucosal ulceration
The overproduction and secretion of gastrin by the gastrinoma
(tumor in the pancreas)
stimulates hypersecretion of hydrochloric acid

17. Alcohol induce peptic ulcer:
Affect to mucosal barrier
Ulcerogenic effects
Result in altering gastric mucosal defense mechanisms

18. Clinical manifestations
Upper abdominal pain occurring 1–3 h after meals
Dyspepsia (discomfort in the upper abdomen).
Anorexia (eating disorder)
weight loss
Nausea
Vomiting
Heartburn
A typical nocturnal pain that awakens the patient from sleep
(especially between 12 AM and 3 AM)
Belching (allowing air in the stomach to come up through the
mouth)
Bloating (uncomfortable sensation of a very full stomach)

20. Complications
 Upper GI bleeding (erosion of an ulcer into an artery)
 Melena/ black-colored stool
 Hematemesis/ vomiting of blood
 Perforation (second to bleeding)
 Anaemia

21. Diagnosis
Rapid Urease Test:
• Considered “gold standard” for detection of H. pylori infection;
>95% sensitivity and >95% specificity.
• Results are not immediate; not recommended for intitial diagnosis;
more expensive than rapid urease test.
Culture test:
• Permits sensitivity testing to determine antibiotic choice or
resistance.
• Results are not immediate; not recommended for initial
diagnosis; more expensive than rapid urease test.

22. Urea Breath Test:
• Results usually take about 2 days
• Less expensive than tests that utilize gastric mucosal biopsy but
more expensive than serologic tests.
• Availability and reimbursement is inconsistent.
Serologic Antibody Tests:
• Detects IgG antibodies to H. pylori in serum, whole blood or urine.
• Qualitative in office tests; provide results quickly (usually
within 15 minutes) but yield more variable results.
• Tests are widely available and inexpensive.

23. Treatment

24. DESIRED OUTCOME:
 Overall treatment is aimed at relieving ulcer pain, healing the ulcer,
preventing ulcer recurrence, and reducing ulcer-related
complications.
 Successful eradication heals ulcers and reduces the risk of
recurrence to less than 10% at 1 year
GOAL OF THE TREATMENT:
 The goal of therapy in H. pylori-positive patients with an active
ulcer, a previously documented ulcer, or a history of an ulcer-related
complication, is to eradicate H. pylori, heal the ulcer, and cure the
disease.
 The goal of therapy in a patient with a NSAID-induced ulcer is to
heal the ulcer as rapidly as possible.

25. Management

28. Non-pharmacological
• Regular small meals are advisable.
• Smoking and alcohol should be avoided.
• Avoid stress
• Coffee or tea should be taken only in moderation, because they are
strong stimulants of acid secretion.
• Late snacks are best avoided, because they stimulate nocturnal
gastric secretion.
• Drink water.
• Patients with PUD should discontinue NSAIDs.

29. Pharmacotherapy

30. H2 receptor antagonists
 These were the first truly effective drugs for the therapy of acid-
peptic disease, and their long history of safety and efficacy.
 Rimetidine .Ranitidine, Famotidine, and Nizatidine are less potent
than proton pump inhibitors but still suppress 24-hour
 Their efficacy appropriate in suppressing nocturnal acid secretion.
Dosage form:
 oral administration. Intravenous and intramuscular preparations of
Cimetidine, Ranitidine, and Famotidine are available.

31. Dose:
 Evening dosing of H2 receptor antagonists is adequate therapy in
most instances.
 single night-time or twice-daily dose, though gastric ulcers may
need larger doses and more prolonged treatment.
 There is some evidence that dosing after the evening meal gives
superior results to bedtime dosage.
 These doses provide healing in about 70% of gastric ulcer patients
after 1 month and in about 80% after a further 2–4 weeks, but
treatment may need to be extended to 12 weeks.
 Therapeutic levels are achieved rapidly after intravenous dosing
 and are maintained for 4–5 hours (Cimetidine), 6–8 hours
(Ranitidine), or 10–12 hours (Famotidine).

32.  Precaution :
 Reduce doses of H2 receptor antagonists in patients with decreased
creatinine clearance.
Interaction:
 Cimetidine, uniquely among the H2-RAs, potentiates the actions of
Warfarin, Theophylline, Phenytoin, beta-blockers and many other
drugs, by inhibiting cytochrome P450-mediated liver metabolism.
Half life: 2–3 hr
Pregnancy category: B

33. Adverse effects:
 Diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation.
 Less common adverse effects include those affecting the CNS (confusion,
delirium, hallucinations, slurred speech, and headaches), which occur
primarily with intravenous administration or in elderly subjects.
 Long-term use of Cimetidine at high doses decreases testosterone
binding to the androgen receptor and inhibits a CYP that hydroxylates
estradiol.
 Clinically, these effects can cause galactorrhea in women and
gynecomastia, reduced sperm count, and impotence in men.
 Several reports have associated H2 receptor antagonists with various blood
dyscrasias, including thrombocytopenia.
 H2 receptor antagonists cross the placenta and are excreted in breast
milk.

34. Drug Dose and frequency
Ranitidine 300 mg at bed time or 150 mg BD; for maintenance
150 mg at bed time.
Parenteral dose—50 mg, i.m. or slow i.v. inj. every 6–
8 hr (rapid i.v. injection can cause hypotension), 0.1–
0.25 mg/kg/hr by i.v. infusion has been used for
prophylaxis of stress ulcers.
Famotidine 40 mg at bed time or 20 mg BD (for healing); 20 mg
at bed time for maintenance; upto 480 mg/day in ZE
syndrome;
parenteral dose 20 mg i.v. 12 hourly or 2 mg/hr i.v.
infusion
Cimitidine Dose: 150 mg at bed time or 75 mg BD; maintenance
75 mg
at bed time.

35. Proton pump inhibitors (PPIs)
 Drugs of first choice.
 These are prefer either complicated or unresponsive to treatment
with H2 receptor antagonists.
 These are FDA-approved for treatment and prevention of recurrence
of NSAID associated gastric ulcers in patients who continue NSAID
use and for reducing the risk of duodenal ulcer recurrence associated
with H. pylori infections.
 In children, omeprazole is safe and effective for treatment of erosive
esophagitis

36. Dosage forms:
 Omeprazole, Esomeprazole, and Lansoprazole available as Enteric-
coated drugs contained inside gelatin capsules.
 Lansoprazole enteric-coated granules supplied as a powder for
suspension.
 Pantoprazole, Rabeprazole, and Omeprazole available as enteric-
coated tablets.
 Powdered drug combined with sodium bicarbonate Omeprazole.
 Pantoprazole is available in intravenous form
Dose:
 Pantoprazole is directed to gastric ulcers in 8 weeks, but
Rabeprazole takes rather longer (6 and 12 weeks, respectively).

37. Interaction:
 Proton pump inhibitors can interact with warfarin & diazepam
 Esomeprazole and Omeprazole and pantoprazole interacts
Cyclosporine inhibits CYP2C19
 Decreasing the clearance of Disulfiram, Phenytoin,
 These are induces the expression of CYP1A2, thereby increasing the
clearance of imipramine, several antipsychotic drugs, tacrine, and
theophylline).
Contraindication:
 Hypersensitivity reactions, including anaphylaxis, anaphylactic
shock, angioedema, bronchospasm, acute interstitial nephritis, and
urticaria
Pregnancy category: B

38. Precaution:
 Care should be taken patient who has Renal impairment , liver
disease and hypersensitivity to IV.
ADR:
 The most common are nausea, abdominal pain, constipation,
flatulence, and diarrhea.
 Subacute myopathy, arthralgias, headaches, and rashes also have
been reported. Gynaecomastia (breast enlargement).
Half life:
 Oral or IV, 1 hour
 Oral or IV, slow metabolizers, 3.5 to 10 hours
 Pediatrics, 0.7 to 5.34 hours

39. Drug Dose and frequency
Omeprazole 20–40 mg OD
Lansoprazole 15–30 mg OD
Pantoprazole Dose: 40 mg OD
Rabeprazole 20 mg OD; ZE syndrome — 60 mg/day

40. Mucosal protectents
Sucralfate
 It is a basic aluminium salt of sulfated sucrose.
 Sucralfate may offer an advantage over proton pump inhibitors and
H2 receptor antagonists for the prophylaxis of stress ulcers
 The process can be inhibited by sulfated polysaccharides. acid-
induced damage, pepsin-mediated hydrolysis of mucosal proteins
contributes to mucosal erosion and ulcerations.
Dose :
 Stress ulcer; Prophylaxis:1 gram NG or ORALLY empty stomach
1 hour before the 3 major meals and at bed time for 4–8 weeks.
 Infant, 40 mg/kg/day NG or ORALLY in 4 divided doses
 Children, 40 to 80 mg/kg/day NG or ORALLY in 4 divided doses;
maximum 4 g/day

41. Half life: 2-4 hr
Precaution:
 Care should be taken patient with chronic renal failure.
Contraindication:
 Hypersensitivity to sucralfate or any of its excipients.
Adverse drug reaction:
 Common :Constipation (2% )
 Serious: Hyperglycemia, In diabetic patient
Pregnancy category: B

42. ANTACIDS
 These are indicated as sole therapy in young patients (under 40
years) and those with chronic, stable, mild symptoms.
 sodium bicarbonate effectively neutralizes acid.
Contraindication:
 chloride loss, by vomiting
Precaution:
 renal impairment and sodium-restricted diet patients.
ADR:
 Cellulitis, Injection site extravasation, Skin ulcer, Tissue necrosis,
Metabolic alkalosis.
Pegnancy category: C

43. H Pylori treatment
 High eradication rates are achieved by a short course of triple
therapy consisting of a PPI, clarithromycin and amoxicillin or
metronidazole in a twice-daily simultaneous regimen.
 European guidelines recommend 1 week of therapy.
 US guidelines recommend 10–14 days of therapy and achieve 7–9%
better eradication rates.
Triple therapy consists of:
 OCA: omeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1
g or
 OCM: omeprazole 20 mg, clarithromycin 250 mg and
metronidazole 400 mg.

44.  Amoxicillin is preferred over clarithromycin for initial eradication
because bacterial resistance is almost absent and it has fewer
adverse effects.
 Substitution of Clarithromycin 250 to 500 mg four times a day for
tetracycline yields similar results after unsuccessful initial treatment
with a PPI–amoxicillin– Clarithromycin regimen.
 Second-line therapy should be instituted with bismuth subsalicylate,
Metronidazole, tetracycline, and a PPI for 14 days.
 A lower dose of clarithromycin (250 mg twice daily) is effective and
recommended when combined with Metronidazole 500 mg twice
daily to achieve consistency.
 In patients with hypersensitivity to penicillin, the OCM regimen or
substitution of amoxicillin from the OCA regimen with tetracycline
500 mg twice daily is used.

45. • Recommended second-line triple therapy regimens include a PPI,
amoxicillin or tetracycline and Metronidazole.
AMOXICILLIN:
Half life: immediate-release, 61.3 minutes, extended-release, 1.5
hours.
Precaution:
 Severe renal impairment, erythematous skin rash.
Contraindication:
 Serious hypersensitivity reactions, such as anaphylaxis and Stevens-
Johnson syndrome, to amoxicillin or other beta-lactam antibiotics.

46. Pregnancy category: B
ADR:
 Tetracyclines (decreased antibacterial effectiveness)
 Warfarin (increased risk of bleeding)
 Methotrexate (methotrexate toxicity)
 Piperine (increased bioavailability of amoxicillin)
 Venlafaxine (increased risk of serotonin syndrome).

47. CLARITHROMYCIN
Dose:
 (Immediate-release, triple therapy) Clarithromycin 500 mg,
omeprazole 20 mg, and amoxicillin 1 g orally twice daily for 10
days, followed by an additional 18 days of omeprazole 20 mg once
daily when ulcer present at time of initiation of therapy
Half life: Clarithromycin (250 mg every 12 hours): 3 to 4 hours; (500
mg every 12 hours): 5 to 7 hours
Precaution:
 renal impairment, severe, with or without hepatic impairment

48. Contraindication:
 cholestatic jaundice and/or hepatic dysfunction.
 hypersensitivity to clarithromycin or any component of the product,
erythromycin, or any macrolide antibiotics.
 QT prolongation or ventricular cardiac arrhythmias.
Interaction:
 Colchicine may result in increased colchicine plasma concentrations
and increased risk of toxicity.
 Ergot derivatives and Macrolide antibiotics may result in an
increased risk of acute ergotism (nausea, vomiting, vasospastic
ischemia).
 Simvastatin may result in an increased risk of myopathy or
rhabdomyolysis.
 Fluconazole may result in increased clarithromycin exposure and an
increased risk of cardiotoxicity

49. ADR:
Common
 Gastrointestinal: Abdominal pain, Diarrhea , Disorder of taste,
Indigestion, Nausea, Vomiting.
 Neurologic: Headache.
Serious
 Cardiovascular: Death, Cardiovascular, Prolonged QT interval.
 Hepatic: Hepatitis.
 Pregnancy category: C

50. METRONIDAZOLE
Dose:
 8 hours, 75 hours, adults; 35 hours, neonates 28 to 30 weeks; 25
hours, neonates 32 to 40 weeks.
Dosage form:
 Intravenous ,Oral, Topical, Vaginal
Half life:
 8 hours (range 6 to 12 hours)
 75 hours, adults; 35 hours, neonates 28 to 30 weeks; 25 hours,
neonates 32 to 40 weeks.
Precaution:
 Hepatic disease, peripheral neuropathy, skin reactions, renal disease

51. Contraindication:
 hypersensitivity to Metronidazole.
 pregnancy, first trimester, in patients being treated for
trichomoniasis.
Interaction:
 Mesoridazine and QT interval prolonging drugs may result in
increased risk of QT-interval prolongation.
 Disulfiram may result in CNS toxicity (psychotic symptoms,
confusion).
 Ziprasidone may result in increased risk of QT-interval
prolongation.
 WARFARIN may result in increased risk of bleeding
 Gonadotropin Releasing Hormone Agonists may result in increased
risk of QT-interval prolongation.

52. ADR:
Common
• Gastrointestinal: Abdominal discomfort , Abnormal taste in mouth
, Diarrhea , Nausea
• Immunologic: Jarisch Herxheimer reaction
• Neurologic: Dizziness
Serious
• Stevens-Johnson syndrome, Toxic epidermal necrolysis,
Leukopenia
Hepatic failure, acute, Hepatotoxicity. Ototoxicity, Disorder of
optic nerve.
Pregnancy category:
 Fetal risk has been demonstrated

53. BISMUTH SUBSALICYLATE
Dose:
 Quadruple therapy, 300 mg orally 4 times per day in combination
with tetracycline 500 mg orally 4 times per day, metronidazole 500
mg orally 3 or 4 times per day OR 250 mg orally 4 times per day,
and standard-dose proton pump inhibitor orally twice daily.
Continue regimen for 10 to 14 days.
Half life:
 2-5 hours
Precaution:
 colitis or other gastrointestinal mucosa abnormalities
 anticoagulants, gout, or diabetes medications
 previous hypersensitivity

54. Contraindications:
 children or teenagers with or recovering from influenza or varicella.
 hypersensitivity to the bismuth subsalicylate or salicylates.
ADR:
Serious
 Neurotoxicity (rare).
Pregnancy category: B

55. Proton Pump Inhibitor–Based Three-Drug Regimens:
Drug Dose Frq Days
Clarithromycin 500 mg BID 10–14 days
PPI Standard dose BID 10–14 days
Amoxicillin 1 gm BID 10–14 days
Metronidazole 500 mg BID 10–14 days

56. Bismuth-Based Four-Drug Regimens:
Drug Dose Frq Days
Bismuth subsalicylate 525 mg QID 10–14 days
Metronidazole 250–500 mg QID 10–14 days
Tetracycline plus 500 mg QID 10–14 days
PPI Standard dose QID 10–14 days
H2RA Standard dose BID 4–6 wks

58. References:
1. Manual of pharmacology and therapeutics by Goodman and
gilman’s Drugs affecting Gastrointestinalfunction Pg: 621-27.
2. Clinical pharmacy and therapeutics by roger walker Peptic ulcer
disease Pg: 162-173.
3. Pathology and therapeutics for pharmacist by Russell J Greene,
peptic ulcer disease, Pg: 97-107.
4. Applied therapeutics by Marry Anne Koda Kimble upper gastro
intestinal disorder.
5. Pharmacotherapy a Phathophysiologic approach by Joseph T
Dipiro, Peptic ulcer disease, Pg: 570-85.
6. Micromedex.
7. Pubmed.
8. Medscape.

59. Thank you