Peptic Ulcer

Disease
Vanessa Ting Ching Ching
Introduction
 Heterogeneous group of disorders involving upper GI
tract
 Caused by imbalance between aggressive factors
and defensive factors
 Acute: specific patient population and clinical
situation (eg stress ulcers)
 Chronic: usually H.Pylori or NSAID ulcers with risk
factors. Has remission and recurrence episodes
Physiology of upper GI tract
 Stomach consists of:
 Cardia
 Body – contains
parietal cells (secrete
acid and intrinsic
factor) and chief cells
(secrete pepsinogen)
 Antrum – contains G
cells (secrete gastrin)

Adapted from www.nlm.nih.com

Aggressive factors
 K+-H+-ATPase pump secretes acid and is
stimulated by:
 Acetylcholine – neurologic impulses of sight,
smell and taste of food or due to food
distension or food protein.
 Gastrin - released by stimulation of Ach on
antral G cells
 Histamine - Secreted by parietal cells
 Pepsinogen
 forms pepsin in pH<3.5
 combines with acid to form proteolytic
complex
Defensive factors
 Prostaglandin E and somatostatin
 inhibit gastric acid secretion, maintain mucosal blood
flow, and stimulate production of mucus and bicarbonate
 epithelial cells and mucous cells
 secrete mucus
 Gastric mucus
 traps microorganisms, prevents back difussion of H ions
from the mucosa, and acts as a lubricant
 Bicarbonate secretion
 neutralises H ions
 Network of vascular capillaries
 transport oxygen and substrates to the mucosa and
remove acids
Risk factors
Established
 Age >60 years
 H.pylori infection
 Previous PUD and UGIB
 Concomitant corticosteroid
therapy
 High dose, multiple NSAID
use
 Concomitant anticoagulant
use / coagulopathy
 Chronic major organ
impairment
Possible
 NSAID-related dyspepsia
 Duration of NSAID use
 Cigarette smoking
 Rheumatoid arthritis
Questionable
 Alcohol consumption
 Psychological stress
 Dietary factors
* Combinations of risk
factors are additive
Signs and Symptoms
 Epigastric pain  Weight loss
(burning, cramping,  Complications eg
fullness) ulcer bleeding,
 Nocturnal pain that perforation,
awakes patient penetration,
 Heartburn, obstruction
belching, bloating
 Nausea, vomiting,
anorexia
Diagnosis
Laboratory Tests Other diagnostic tests
 Gastric acid secretory  Fibreoptic upper
studies endoscopy
 Fasting serum gastrin  routine single-barium
concentrations contrast techniques
 FBC – low haematocrit
and haemoglobin
 Tests for H.pylori
Treatment Aims
 Decrease gastric acidity
 Inhibit gastric secretion (PPIs, H2-antagonists)
 Neutralise gastric acid (antacids)
 Duodenal ulcers associated with ↑acid secretion
 Increase mucosal defences
 Protect GI mucosa (sucralfate, misoprostol)
 Gastric ulcers associated with normal/↓acid secretion
 Eliminate H.pylori
 Antibiotics, bismuth
Proton Pump Inhibitors
 Potency: esomeprazole=rabeprazole>
pantoprazole=lansoprazole=omeprazole
 Inhibit K+H+ATPase covalently
 Up to 72 hours antisecretory effect
 Faster onset compared to H2-antagonists,
but similar rate of healing
 Metabolised by CYP450 system therefore
drug interactions with diazepam, phenytoin,
warfarin, tolbutamide
 Except pantoprazole – metabolised by
cytosolic sulfotransferase
H2-Receptor Antagonists
 Potency: famotidine > nizatidine=ranitidine
>cimetidine
 Block histamine receptors – decrease acid secretion
 Cimetidine metabolised by CYP450 – decrease
theophylline elimination by 20-30%
 Cimetidine, ranitidine excreted by renal tubular
secretion – decrease procainamide elimination
 Alter gastric pH – decrease ketoconazole absorption
Sucralfate
 At pH 2-2.5, binds to damaged and ulcerated
tissue thus creates physical barrier
 Take with an empty stomach to prevent binding
to phosphate and protein in food
 Efficacy same as H2-antagonists, but requires
complicated dosage regimens
 Multiple daily doses, large size
 Affect bioavailability of other drugs
 Space out 2 hours before sucralfate
 Consider other antiulcer therapy if giving
fluoroquinolones
 Misoprostol
 Synthetic PGE1 analogue, inhibits gastric
acid production
 dose-dependent – 50-200mcg
 cytoprotective – >200mcg

 Causes dose-dependent diarrhoea

 take with meals or at bedtime
 Uterotropic – contraindicated in pregnant
women
Bismuth
 Antidiarrhoeal agent with ulcer-healing effects
 Antibacterialeffect
 Local gastroprotective effect
 Stimulates endogenous PGs

 Used in combination regimens for eradication

of H.pylori
 Safe but may cause salicylate sensitivity
Antacids
 Neutralize acids, cytoprotective (stimulates PG
production), stimulate restitution of gastric mucosa
 Effective at low doses; as effective as H2-
antagonists but short duration of action (~2hrs)
 MgOH – diarrhoea; AlOH – constipation; CaCO3 –
↑gastric acid production at ↑doses; NaCO3 –
systemic alkalosis at prolonged periods
 ↑ gastric pH: ↓bioavailability of ketoconazole;
alter profile of e/c drugs; form complex with
fluoroquinolones and tetracyclins
H. Pylori infection
 Spiral Gram negative bacilli that colonizes the
body of the stomach
 Transmission: oral-oral, fecal-oral, iatrogenic
 Direct mucosal damage
 By cytotoxins, bacterial enzymes and
adherence to stomach wall
 Altered inflammatory response
 Cell-mediated immune mechanisms or
phagocytosis
 Increased gastric acid secretion
 HP products eg ammonia
 Detection of H.pylori
Test Description Comments
Histology Microbiologic examination Gold standard; >95% sensitive and
specific; results are not immediate
Culture Culture of biopsy Sensitivity testing; results are not
immediate; tests for active infection
Biopsy urease Detects ammonia >90% sensitive and specific; easily
released by HP urease performed; rapid results
Antibody Detects antibodies to HP Quantitative; unable to determine if
detection in serum antibody is caused by active or cured
infection
Urea breath HP urease breaks down Tests for active HP infection; 95% sensitive
test ingested labeled C-urea, and specific; results take about 2 days
labeled CO2 exhaled

Stool antigen Identifies HP antigen in Tests for active HP infection; as effective as

stool urea breath test

 Adapted from Pharmacotherapy: A pathophysiologic approach

Treatment of H.pylori
 Eradication of H.pylori with combination therapy
= ↓ulcer recurrence
 7-day treatment is minimally effective but 14-
day treatment is recommended
 Use of single antibiotic has variable and
marginal eradication rates and ↑antibiotic
resistance
 Clarithromycin is single most effective antibiotic
 H.Pylori Eradication Regimens
Regimen Duration Comments
Omeprazole 20mg bd + 1 week All combos of 3 antibiotics
clarithromycin 500mg bd + similarly effective; usually
metronidazole 400mg bd or clarith + amoxy; ↑eradication
amoxycillin 500mg bd rates with clarith1.5g/day

Omeprazole 20mg bd + amoxycillin 2 weeks Marginal and variable

500mg tds or clarithromycin 500mg
tds
Bismuth salicylate 120 mg qid +
metronidazole 400mg tds +
amoxycillin 500mg tds or tetracycline
500mg tds
Ranitidine 300mg + amoxycillin
500mg tds + metronidazole 400mg
tds
 Adapted from Pharmacotherapy: A pathophysiologic approach
eradication rates
2 weeks Similar to PPI-based triple-
therapy; tetracycline more
effective than amoxycillin
2 weeks Better eradication rate using
PPI
NSAID use
 2 mechanisms:
1. Direct irritant effect –
acidic properties
2. COX-1 inhibition –
inhibition of PG release
causing decrease in GI
mucosal integrity and
platelet homeostasis
 Leukotrienes stimulate
neutrophil adherence
which damages
endothelium
Taken from www.medscape.com
Treatment of NSAID Ulcers
 Withdrawal/reduction of NSAID
 Replace with paracetamol/selective COX-2
inhibitors
 Duodenal ulcers/smaller gastric ulcers – full
dose H2-antagonist for min 8 weeks
 Ranitidine 150mg bd
 Gastric ulcers/continued NSAID use – PPI for 8
weeks
 Omeprazole 20mg/day
 Misoprostol 800mcg/day in divided doses
Zollinger-Ellison Syndrome
 Non-β-islet cell tumours (gastrinoma) secrete
additional gastrin –hyperstimulation of gastric acid
secretion
 Characterised by severe recurrent PUD
 Basal acid output >15mEq/h; fasting serum gastrin
>1000 pg/mL
 Treat with high dose PPIs in divided bd/tds doses
 Eg omeprazole 60-80mg/day, up to 360mg/day
 Octreotide (synthetic somatostatin) inhibits gastric acid
secretion
 s/c 100-250mcg tds
Acute Upper GI Bleeding
 Endoscopic therapy if active bleeding,
exposed visible vessel or clot-covered ulcer
 Adrenaline injection up to 15 mL
 Concomitant high-dose continuous IV infusion
of PPI
 Omeprazole 80mg load, then 8mg/h for 3 days
 Less severe bleeders: IV 40mg bd
 Continue PPI for 4-6 weeks then H2-antagonist
for another 4-6 weeks
Stress Ulcers
 Acute in nature; occur in critically-ill patients
 ↓ gastric mucosal blood flow in haemorrhagic,
cardiogenic and septic shock
 ↓ rate of proliferation and cellular turnover of
gastric mucosa
 No prostaglandin and mucous formation
 Risk factors: mechanical ventilation >48 hrs,
high-dose CCS therapy, sepsis, coagulopathy
 Others: shock, burns, multiple organ failure,
trauma, CNS injury
Stress Ulcer Prophylaxis
Improve physiological Adequate neutralisation of
conditions gastric acid
 Inotropic drugs  At pH 3.5-4, ↓frequency of
 Vasodilators bleeding; at pH<7, impaired
 Intravascular volume clot stability
 Sucralfate 1g qid via
replacement
 Prevention of infection nasogastric tube
 IV ranitidine (bolus 50mg
 Analgesia and sedation
tds or infusion 6.25-
 Enteral nutrition
12mg/h)
 IV omeprazole 40mg od has
↑antisecretory effects but
also ↑nosocomial
pneumonia
References
 Dipiro JT, Talbert RL, Yee GC, et al,
Pharmacotherapy: A pathophysiologic approach. 6th
edition. New York: McGraw-Hill; 2006
 Koda-Kimble MA. Applied therapeutics: the clinical use
of drugs. 8th edition. USA: Lippincott Williams &
Wilkins; 2005.
 Kew ST, Tan SS et al. Consensus of Management of
Peptic Ulcer Disease. Malaysian Clinical Practice
Guidelines.
 Rang, Dale, Ritter, Moore. Pharmacology. Elsevier
Science Limited; 2003