Peptic ulcer, GERD; its management

1. Drug for peptic ulcer & GERD

2. 2
Gastric Mucus-Bicarbonate Barrier

3. 3
Synthesize and
secrete the HCl acid
responsible for the
acidic pH in the
gastric lumen.
Synthesize and
secrete the protease
precursor known as
pepsinogen.
Produce alkaline
mucus that covers
mucosa layer
Exocrine gland cells of gastric pits

4. Gastric Glands and secretions

5. Gastric secretion phases
Gastric acid secretion can be divided
into three phases:
• Cephalic phase mediated by the CNS
– triggered by smelling, chewing or even the thought of food.
– Mediated by the vagus and acounts for 10- 30% of the acid
secreted).
• Gastric phase triggered by the presence of food in
– the stomach (both chemical and mechanical sensing are
involved).
– Accounts for 70-90% of the acid secretion
• Intestinal phase.
– Presence of chyme,
– Most probably amino acids, in the intestine triggers approximately 5% of
the gastric acid secretion.

6. G
gastrin
circulation
HCl
vagus
nerve
FOOD
Distension
Peptides
2. Gastric Phase of Gastric
Secretion (approx 60% of
total)
(initiated by gastric events)
G
gastrin
circulation
HCl
vagus nerve
1. Cephalic Phase of Gastric
Secretion (approx. 30% of
total)
(initiated by brain)
Functional Phases of Gastric Secretion

7. PUD
• Peptic ulcer disease (PUD) = Mucosal defect in
the gastrointestinal tract (gastric or duodenal)
exposed to acid and pepsin secretion
• Gastritis is the precursor to PUD and it is
clinically difficult to differentiate the two

8. Differentiating gastric from peptic
ulcer disease
• Duodenal ulcers - age 25-75 years.
• Gastric ulcer - age 55-65 years
• Pain awakening patient from sleep between
12-3 a.m. present in 2/3 duodenal ulcer
patients and 1/3 gastric ulcer patients

9. Case Presentation
Mr. X is a 45 year old male who
presents to your clinic with epigastric
abdominal pain x 2 weeks.
What is your initial differential diagnosis at this
point given the limited information?

10. Initial Differential Diagnosis
More Common:
• Gastroesophageal reflux
disease
• Nonulcer dyspepsia/
Gastritis
• Ulcer disease
• Gastroenteritis
• Biliary colic or cholecystitis
• Pancreatitis
• Irritable bowel disease
Less Common:
• Mesenteric Ischemia
• Stomach/Pancreas/
Hepatobiliary cancers
• Atypical manifestion
CAD/angina
• Posterior Wall AMI
• Aortic Aneurysm
• Inflammatory Bowel Dz

11. Mr. X
• Mr. X is a 45 year old male who presents to your
clinic with epigastric abdominal pain x 2 weeks. He
describes it as a burning pain which is non-radiating
and is worse after he eats. He has frequent belching
with bloating sensation but denies nausea, vomiting,
diarrhea, constipation, or weight loss. He has tried
antacid which do help a little.
• Which symptoms support the possible diagnosis of
PUD?

12. Signs and Symptoms of PUD
• Epigastric pain is most common symptom
• Pain described as burning
• May radiate to the back (consider penetration)
• Occurs 1-3 hours after meals or at night
• Relieved by food, antacids (duodenal), or vomiting
(gastric)
• Dyspepsia including belching/ bloating
• Hematemesis or melena with GI bleeding

13. Clinical Pearls
• NSAID-induced gastritis or ulcers are
frequently “silent”
• Dyspeptic signs are non-specific – approx 20-
25% of patients with sign will have peptic
ulcer on further workup

14. Mr X History
PMH: HTN stable, Osteoarthritis in knees, treated for
an ulcer 3 years ago
Meds: Hydrochlorothiazide, ibuprofen
Soc HX: Married, employed as bank manager, smokes
1ppd x 20years, drinks 2 beers per day, and 2-4 cups
coffee per day
What risk factors can you identify for PUD?

15. Common Risk Factors for Gastric Mucosal
Disruption
• H.pylori
• NSAIDs/ASA (even at low dose)
• Coffee/Caffeine
• Ethanol
• Tobacco
• Severe physiologic stress (Burns, CNS trauma,
Surgery, Severe medical illness)
• Steroids

16. Pathophysiology
PUD is a result of
acid/pepsin production
imbalance with
protective mechanisms
such as mucous
production

17. NSAIDs
• Approximately 15% of patients on long-term NSAID
develop PUD
• NSAIDs/ASA - ↓prostaglandin (PG) by inhibiting the
cyclooxygenase (COX) enzymes
• Three isoenzymes COX-1, COX-2, COX-3
• COX-1 → PG production in gastric mucosa
• COX-2 specific NSAIDs reduce GI side effects –
cardiovascular side effects have limited use

18. Individual NSAID Risk
High Risk
• Piroxicam
• Ketorolac
• Indomethacin
Lower Risk
• COX-2 specific - Celecoxib
• Ibuprofen (< 1500mg/d)
• Relatively selective COX-2
nabumetone/etodolac
/meloxicam

19. Discovery of Helicobacter pylori
• “Two Australian physicians won the 2005
Nobel Prize in Medicine or Physiology for
showing - that many ulcers are the result of a
bacterial infection.”
“Robin Warren
and Barry
Marshall's work
on ulcers was
pioneering”Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-
/2/hi/asia-pacific/4307826.stm
Published: 2005/10/04 10:39:09 GMT
© BBC MMVII

20. H. pylori
• Curvelinear, gram (-) rod with
flagella
• H pylori is most common
cause of PUD
• Transmission route fecal-oral
• Secretes urease →convert
urea to ammonia
• Produces alkaline
environment enabling survival
in stomach.

21. H. pylori
• Higher prevalence in Low socio-economical status
• H pylori (+) is normally present in 60% general
population
• Almost all duodenal and 2/3 gastric ulcer pt’s
infected with HP
• Asymptomatic in approx 70% of those who are H
pylori (+)
• Considered class 1 carcinogen → gastric cancer

22. Differentiating between H. pylori and
NSAID-induced ulcer
Ulcers associated with H.
pylori
• more often in
duodenum
• often superficial
• less severe GI bleeding
Ulcers associated with
NSAIDs
• more often in stomach
• often deep
• more severe GI bleeding
• sometimes
asymptomatic

23. Other Disease Conditions Associated with
PUD
• Hypersecretory states: Gastrinoma (Zollinger-
Ellison syndrome) or multiple endocrine
neoplasia (MEN-I)
• Diseases assoc. with increased risk of PUD:
cirrhosis, chronic pulmonary disease, renal
failure

24. Mr. X Physical Exam
• VS: BP 137/82, HR 85,, RR 14
• Heart: WNL
• ABD: Soft, NABS, mild-moderate epigastric, no
HSM or masses, no acute abd signs
• Skin: no pallor
• Rectal: stool brown, heme (-), no masses
What are typical PE findings in PUD?

25. Physical Exam Findings
In uncomplicated PUD exam findings few and
non-specific:
• Epigastric tenderness - usually mild.
• Bowel sounds - normal.
• Rectal exam may show melena/guaiac+ stool
from occult blood loss
• Signs of peritonitis with perforation

26. If Mr. X Hemoccult is Positive
What PE findings do you want to specifically
document if Mr. X is Heme (+) indicating a
possible active GI bleed?
• Look for signs of volume depletion:
tachycardia, hypotension, orthostatics, skin
turgor, MM appearance
• Look for signs of anemia: conjunctiva or skin
pallor, new heart murmur

27. Lab Studies to Evaluate PUD
• CBC - evaluate acute/chronic blood loss
• H. Pylori
- Serologic antibody test for HP – does not
determine if active HP infection
- Fecal antigen test tests for active HP
- Urea breath test tests for active HP

28. H. Pylori Serology Antibody Test
• Office based serology tests faster but less
accurate than lab based ELISA tests
• Sensitivity and specificity of approx 90%
• Not useful for evaluating eradication -
antibody levels can persist for a long time,
need serial titers to evaluate

29. When is a Serology Test Useful?
Not useful in
• Populations with low
disease prevalence
• Elderly populations to
detect active disease
Useful in
• Patients who never
received H. pylori
treatment
• Symptomatic patients
not using NSAIDs- if
negative serology –
unlikely PUD

30. H. Pylori Stool Antigen (HpSa) Test
• Useful in initial diagnosis + confirmation of
eradication
• Sensitivity of 91% and a specificity of 92%*
• Test requires collection of stool sample
*Gisbert JP, Pajares JM. Stool antigen test for the diagnosis of Helicobacter
pylori infection: a systematic review. Helicobacter 2004;9(4):347-68

31. Urea Breath Test
• Useful for initial diagnosis + confirmation of eradication
• Sensitivity and specificity over 90%*
• Urease activity is present in the stomach in those infected
with H pylori
• Ingest urea labeled with radioactive carbon
• Hydrolysis of urea → labeled carbon dioxide (CO2)
• Rapidly absorbed into bloodstream and within a few minutes,
appears in breath
*Gatta L, Vakil N, Ricci C, et al. A rapid, low-dose, 13C-urea tablet for the detection of Helicobacter pylori
infection before and after treatment. Aliment Pharmacol Ther 2003;17(6):793-8

32. Breath Test Compared to HpSa
• Requires more patient preparation
• More expensive
• Number of drugs can adversely affect accuracy
• Antibiotics and bismuth → stop for 4 weeks
• Proton pump inhibitors → stop for 7 days
• Patients need to fast for at least 6 hours.
• Breath test cannot be used in pregnant women

33. Imaging Studies
• Chest x-ray if perforation is suspected to
detect free abdominal air
• Upper gastrointestinal series
– Performed by experienced radiologist is close to
diagnostic accuracy of endoscopy
– Not as sensitive as endoscopy in diagnosis of small
ulcers (<0.5 cm)
– Unable to obtain biopsy to rule out malignancy

34. Endoscopy
Endoscopy indicated in following high risk patients:
• >50 years old with new-onset dyspepsia
• Dyspepsia with dysphasia and/or weight loss
• Evidence of GI bleeding
• Failed appropriate trial of empiric therapy
• Using NSAIDs or other high risk meds
• Signs of UGI tract obstruction (early satiety, vomiting)
• Ethnic background assoc. with increased risk UGI
malignancies
Excerpts from Guidelines prepared by The Standards of Practice Committee of the American Society for
Gastrointestinal Endoscopy

35. Treatment Options……….

36. H2 ANTAGONISTS
• These are the first class of highly effective
drugs for acid-peptic disease, but have been
surpassed by proton pump inhibitors (PPIs).
• Four H2 antagonists cimetidine, ranitidine,
famotidine and roxatidine.

37. Pharmacological actions
H2 blockade Gastric secretion
block histamine-induced gastric
secretion,
Blocker all phases (basal, psychic,
neurogenic, gastric) secretion.
block cardiac stimulation More effect on nocturnal acid secretion
uterine relaxation (in rat) Inhibition is dose-dependently
bronchial relaxation it does not interfere with vit B12
absorption.
Hypotension 60–70% inhibition seen on 24 hr acid
output
Useful in NSAIDs, cholinergic,
histaminergic induce ulcers

38. PK
• Cimetidine is adequately absorbed orally
• bioavailability is 60–80% due to first pass hepatic
metabolism.
• Absorption is not interfered by presence of food
in stomach.
• It crosses placenta and reaches milk, but
penetration in brain is poor because of its
hydrophilic nature.
• The elimination t ½ is 2–3 hr.
• Dose reduction is needed in renal failure.

39. ADR & Interactions
• Headache, dizziness, bowel upset, dry mouth,
rashes.
• It has antiandrogenic action (displaces
dihydrotestosterone from its cytoplasmic
receptor), increases plasma prolactin and inhibits
degradation of estradiol by liver.
• High doses given for long periods have produced
gynaecomastia, loss of libido, impotence and
temporary decrease in sperm count.

40. Interactions
• It is a microsomal enzyme inhibitor.
• It inhibits the metabolism of many drugs so that
they can accumulate to toxic levels, e.g.
theophylline, phenytoin, carbamazepine,
phenobarbitone, sulfonylureas, metronidazole,
warfarin, imipramine, lidocaine, nifedipine,
quinidine. Metabolism of propranolol and
diazepam
• Antacids reduce absorption of all H2 blockers.
• Ketoconazole absorption is decreased by H2
blockers due to reduced gastric acidity.

41. Ranitidine Famotidine Roxatidine
About 5 times more
potent than cimetidine
5–8 times more potent
than ranitidine
twice as potent and longer
acting than ranitidine
t ½ of 2–3 hr t ½ of 2.5–3.5 hr Same as ranitidine
No antiandrogenic action No antiandrogenic action No antiandrogenic action
Lesser permeability into
the brain
The oral bioavailability of
famotidine is 40–50%,
Same as ranitidine
side effects headache,
diarrhoea/constipation,
dizziness
headache, dizziness,
bowel upset, rarely
disorientation and rash
Same as ranitidine

43. Indications
• Duodenal ulcer: H2 blockers produce rapid and marked pain relief (within
2–3 days).
• Gastric ulcer Healing: H2 blockers can heal NSAID associated ulcers, but
are less effective than PPIs or misoprostol.
• Stress ulcers and gastritis: Intravenous infusion of H2 blockers used
prevents the gastric lesions and haemorrhage as well as promotes healing
of erosions that have occurred.
• Zollinger-Ellison syndrome: high dose of H2 blockers are used to control
hyperacidity and symptoms in many patients, but PPIs are the drugs of
choice. Definitive treatment is surgical.
• Gastroesophageal reflux disease (GERD): H2 blockers are indicated only in
mild or stage-1 cases of GERD.
• Prophylaxis of aspiration pneumonia: H2 blockers are used reduce the
risk of aspiration of acidic gastric contents during anaesthesia and surgery.

44. PROTON PUMP INHIBITORS (PPIs)
• The parietal cells of the stomach secrete H+
(Proton) with the help of an enzyme H+/K+
ATPase (proton pump).
• These drugs should be administered
approximately 1 hour before breakfast
because they inhibit only those acid secretary
proton pumps which are in active stage.

45. • As such, inhibition of HCl secretion occurs within
1 hr, reaches maximum at 2 hr, is still half
maximal at 24 hr and lasts for 2–3 days.
• Since only actively acid secreting proton pumps
are inhibited, and only few pumps may be active
during the brief interval that the PPI is present
(all have 1–2 hours plasma t½), antisecretory
action increases on daily dosing to reach a
plateau after 4 days.
• At steady state all PPIs produce 80–98%
suppression of 24 hour acid output with
conventional doses.
• Secretion resumes gradually over 3–5 days of
stopping the drug.

46. • These drugs are relatively safe in renal and
mild to moderate hepatic impairment, while
in severe hepatic impairment dose should be
monitored.
• They are microsomal enzyme inhibitors;
therefore cause many drug interactions.
• They increase the plasma level of warfarin,
benzodiazepine and phenytoin, which may
leads to toxicity.

47. Side effects
• loose stools, abdominal pain, joint pains
headache and dizziness.
• Prolonged use of PPI may cause atrophic
gastritis, Achlorhydria, hypogastrinaemia and
vitamin-B12 deficiency.

49. The main indications of proton pump inhibitors
are:
• Peptic ulcer
• Bleeding peptic ulcer
• Stress ulcers
• Gastroesophageal reflux disease(GERD)
• Zollinger-Ellison syndrome
• Aspiration pneumonia

50. ULCER PROTECTIVES
Sucralfate
• It is a basic aluminium salt of sulfated sucrose.
• It forms sticky gel in stomach after being mixed
with gastric secretions.
• This gel forms a layer over the ulcerative region of
the stomach, forms a pseudo-barrier and protects
it at least for 6 hours.
• It does not neutralize acid in the stomach but
delays the gastric emptying, which prolongs its
stay over the ulcer area; thereby increasing the
duration of action.

51. • It also promotes the secretion of mucosal
prostaglandin and bicarbonate for better
healing.
• The GIT absorption is poor; the maximum
amount of sucralfate is excreted through
feaces.

52. • The major indications are:
– Upper GI bleeding.
– Prevention of stress induced GI bleeding.
– Gastritis
– Gastropathy due to bile reflux.
– Gastric and duodenal ulcer.

53. • It is given in a dose of 1gm QID in empty
stomach (at least 1 hour before meals)
followed by maintenance dose at 1gm BD.
• Topical application of sucralfate is used in
burns, bedsores, diabetic/radiation ulcers,
excoriated skin, etc. where it forms a
protective layer.
• The common Side effects are constipation and
dry mouth.

54. Colloidal bismuth subcitrate
• The CBS is water-soluble and works at pH < 5.
• Probably it acts like sucralfate; protects GI
erosion and promotes local synthesis of
prostaglandins.
• It is given in a dose of 120 mg QID preferably
in empty stomach.
• The common side effects are diarrhoea,
headache and dizziness.

55. Drug Therapy For Helicobacter-pylori
(H. pylori) Infection

56. The US-FDA approved regimen:
• Lansoprazole 30 mg + Amoxicillin 1000 mg +
clarithromycin 500 mg, all given twice daily for 2
weeks.
National Formulary of India (NFI, 2010):
• Omeprazole 40 mg OD + Metronidazole 400 mg
TDS + Amoxicillin 500 mg TDS 1 week regimen.
• Quadruple drug regimen is advocated when
triple drug regimen fails.
– Commonly employed quadruple drug regimen is CBS
120 mg QID + tetracycline 500 mg QID +
metronidazole 400 mg TDS + omeprazole 20 mg BD.

57. Gastroesophageal Reflux Disease
• Reflux is a very common problem presenting
as ‘heart-burn’, acid eructations, sensation of
stomach contents coming back in the
foodpipe.
• These symptoms are more especially after a
large meal and aggravated by stooping or lying
flat.
• The management of GERD depends upon the
severity of disease.