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 (burning, cramping, fullness)

Nocturnal pain that awakes patient

Heartburn, belching, bloating

Nausea, vomiting, anorexia

Weight loss Complications eg

ulcer bleeding, perforation, penetration, obstruction

Diagnosis

Laboratory Tests Gastric acid secretory

studies Fasting serum gastrin

concentrations FBC – low haematocrit

and haemoglobin Tests for H.pylori

Other diagnostic tests Fibreoptic upper

endoscopy routine single-barium

contrast techniques

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 Antibacterial effect 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

Adapted from Pharmacotherapy: A pathophysiologic approach

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 released by HP urease

>90% sensitive and specific; easily performed; rapid results

Antibody detection

Detects antibodies to HP in serum

Quantitative; unable to determine if antibody is caused by active or cured infection

Urea breath test

HP urease breaks down ingested labeled C-urea, labeled CO2 exhaled

Tests for active HP infection; 95% sensitive and specific; results take about 2 days

Stool antigen Identifies HP antigen in stool

Tests for active HP infection; as effective as urea breath test

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

Adapted from Pharmacotherapy: A pathophysiologic approach

Regimen Duration Comments

Omeprazole 20mg bd + clarithromycin 500mg bd + metronidazole 400mg bd or amoxycillin 500mg bd

1 week All combos of 3 antibiotics similarly effective; usually clarith + amoxy; ↑eradication rates with clarith1.5g/day

Omeprazole 20mg bd + amoxycillin 500mg tds or clarithromycin 500mg tds

2 weeks Marginal and variable eradication rates

Bismuth salicylate 120 mg qid + metronidazole 400mg tds + amoxycillin 500mg tds or tetracycline 500mg tds

2 weeks Similar to PPI-based triple-therapy; tetracycline more effective than amoxycillin

Ranitidine 300mg + amoxycillin 500mg tds + metronidazole 400mg tds

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 conditions

Inotropic drugs Vasodilators Intravascular volume

replacement Prevention of infection Analgesia and sedation Enteral nutrition

Adequate neutralisation of gastric acid

At pH 3.5-4, ↓frequency of bleeding; at pH<7, impaired clot stability

Sucralfate 1g qid via nasogastric tube

IV ranitidine (bolus 50mg tds or infusion 6.25-12mg/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