Peptic Ulcer Disease

Peptic Ulcer Disease Vanessa Ting Ching Ching

Introduction 

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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   

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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 

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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 

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epithelial cells and mucous cells 

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traps microorganisms, prevents back difussion of H ions from the mucosa, and acts as a lubricant

Bicarbonate secretion 

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secrete mucus

Gastric mucus 

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inhibit gastric acid secretion, maintain mucosal blood flow, and stimulate production of mucus and bicarbonate

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 

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Epigastric pain (burning, cramping, fullness) Nocturnal pain that awakes patient Heartburn, belching, bloating Nausea, vomiting, anorexia

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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   

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Increase mucosal defences  

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Inhibit gastric secretion (PPIs, H2-antagonists) Neutralise gastric acid (antacids) Duodenal ulcers associated with ↑acid secretion 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 

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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

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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 

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Used in combination regimens for eradication of H.pylori Safe but may cause salicylate sensitivity

Antacids   

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Neutralize acids, cytoprotective (stimulates PG production), stimulate restitution of gastric mucosa Effective at low doses; as effective as H2antagonists 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   

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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

Test

Detection of H.pylori Description

Comments

Histology

Microbiologic examination Gold standard; >95% sensitive and specific; results are not immediate

Culture

Culture of biopsy

Biopsy urease Detects ammonia released by HP urease

Sensitivity testing; results are not immediate; tests for active infection >90% sensitive and specific; easily performed; rapid results

Antibody detection

Detects antibodies to HP Quantitative; unable to determine if in serum antibody is caused by active or cured infection

Urea breath test

HP urease breaks down Tests for active HP infection; 95% sensitive ingested labeled C-urea, and specific; results take about 2 days labeled CO2 exhaled

Stool antigen

Identifies HP antigen in stool

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

Adapted from Pharmacotherapy: A pathophysiologic approach

Treatment of H.pylori 

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Eradication of H.pylori with combination therapy = ↓ulcer recurrence 7-day treatment is minimally effective but 14day 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 + 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 2 weeks 500mg tds or clarithromycin 500mg tds

Marginal and variable eradication rates

Bismuth salicylate 120 mg qid + 2 weeks metronidazole 400mg tds + amoxycillin 500mg tds or tetracycline 500mg tds

Similar to PPI-based tripletherapy; tetracycline more effective than amoxycillin

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

Better eradication rate using PPI

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2 weeks

Adapted from Pharmacotherapy: A pathophysiologic approach

NSAID use 

2 mechanisms:

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Direct irritant effect – acidic properties COX-1 inhibition – inhibition of PG release causing decrease in GI mucosal integrity and platelet homeostasis Leukotrienes stimulate neutrophil adherence which damages endothelium

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Taken from www.medscape.com

Treatment of NSAID Ulcers 

Withdrawal/reduction of NSAID  Replace

with paracetamol/selective COX-2 inhibitors

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Duodenal ulcers/smaller gastric ulcers – full dose H2-antagonist for min 8 weeks  Ranitidine

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150mg bd

Gastric ulcers/continued NSAID use – PPI for 8 weeks  Omeprazole

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20mg/day

Misoprostol 800mcg/day in divided doses

Zollinger-Ellison Syndrome 

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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

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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 6.2512mg/h)  IV omeprazole 40mg od has ↑antisecretory effects but also ↑nosocomial pneumonia

References 

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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