Treatment of Peptic ulcer Department of Pharmacology

Introduction Peptic ulcer is a disruption of the mucosal integrity of the stomach and/or duodenum Symptoms - Burning epigastric pain exacerbated by fasting and lessened by meals. Normal Peptic ulcer

Genesis of peptic ulcer Genesis of peptic ulcer involves: Imbalance between the mucosal defensive (mucus, bicarbonate, local synthesis of prostaglandins) and damaging mechanisms (acid, pepsin). + Infection of the gastric mucosa with Helicobacter pylori

Gastric mucosal integrity is based on the balance between Defensive mechanisms Prostaglandins – stimulate the secretion of mucus & bicarbonate & inhibit the secretion of acid. Mucus – alkaline, neutralizes acid Bicarbonate ions, trapped in the mucus, create a pH gradient from 1-2 in the lumen to 6-7 at the mucosal surface. Mucous & bicarbonate form a gel like layer protecting the gastric mucosa from acid. Mucosal blood flow Active repair mechanisms Aggressive factors Acid & Pepsin H. pylori infection NSAIDs Smoking frt

Pathogenesis - not really understood Mucosal resistant theory - Defect in the mechanism which normally prevents the gastric secretion from damaging & digesting the mucosa Acid and Pepsin theory - Excessive secretion of acid ( esp: in DU) - ↑ gastrin secretion - ↑ Sensitivity of parietal cells to action of gastrin Infection in the mucosa with bac: H pylori frt

“Leaking roof hypothesis” Excessive acids in the gut lumen act upon weakened mucosa. Mucosa is weakened by bacteria ( H. pylori ) PU - imbalance between mucosal defense factors & aggressive factors Aggressive factors- acid, pepsin, smoking, H pylori, hereditary (blood gp ‘O’, male) frt

Helicobacter pylori Helicobacter pylori, a gram –negative rod, lives in the human stomach exclusively & survives in the highly acidic environment. It is helix-shaped (hence the name helicobacter) & can literally screw itself into the stomach lining to colonize. It can remain dormant & survive for long periods. H. pylori infection can cause gastritis, peptic ulcer, predispose to gastric cancer etc. About 80% of people are infected with H. pylori, but, only 10 – 15% develop peptic ulcer while 60- 70% of peptic ulcer patients are infected with H. pylori. frt

Development of H. pylori induced peptic ulcer Produce ammonia & neutralizes acid Penetration & adherence Proliferate & form infection focus Peptic ulcer frt

Gastric mucosa H. pylori

Physiology of acid secretion: Acid is secreted from parietal cells by a proton pump (H+/K+ ATPase) Receptors for gastrin, histamine (H2), and acetylcholine (M3) are present on the parietal cell, stimulation of which leads to acid secretion. Prostaglandins decrease acid secretion H+/K+ ATPase (the proton pump) exchanges intraluminal K+ for intracellular H+, secreting acid. frt

To achieve relief of pain To heal ulcer To prevent recurrences Aim of therapy To achieve relief of pain To heal ulcer To prevent recurrences frt

Principles of treatment of peptic ulcer To decrease intragastric pH (& inhibit activation of pepsinogen) – Neutralization of secreted acid Reduction of acid secretion To enhance mucosal resistance & protect ulcer area To eradicate H.pylori

Drugs used in the treatment of peptic ulcer Neutralization of secreted acid – Antacids Reduction of acid secretion – Proton pump inhibitors – Omeprazole H2 receptor blockers – Ranitidine Muscarinic (M3) blockers – Pirenzepine To enhance mucosal resistance & protect ulcer area – Mucosal protectives To eradicate H.pylori – Various regimens

Misoprostol Pirenzepine Ranitidine Histamine _ + _ ACh Gastrin _ + + + PGE2 Ranitidine Histamine _ + _ ACh Gastrin H2 M3 _ Adenyl cyclase + + + Ca++ ATP cAMP Ca++ + + + Protein kinase (Activated) Parietal cell K+ H+ K + Proton pump _ Lumen of stomach _ Omeprazole _ Gastric acid Antacid

ANTACIDS

Antacids Antacids are weak bases that neutralize acid and inhibit peptic activity. Magnesium and aluminium salts - Hydroxide / trisilicate / bicarbonate / carbonate – neutralise acid & also adsorb pepsin. Slow onset and long action May promote mucosal defense by PG production. Available as OTC drugs Sodium bicarbonate acts rapidly and relieves pain. As it can lead to systemic alkalosis & release carbon dioxide in the stomach which may stimulate acid production, it is not advised. frt

Antacids … Duration of action: taken on empty stomach - 30 min & after meal – 2h Liquid formulations are more effective & fast acting than solids. Regimen: 7 times/day ADR: Al3+ antacids cause constipation & Mg2+ antacids cause osmotic diarrhoea. Both together in a formulation nullify these side effects. In impaired renal function, aluminium & magnesium may accumulate producing toxicity. By altering pH, may interfere with absorption of concurrently administered drugs. To avoid this, antacids may be taken 1h before or 3 h after ingestion of other drugs.

Antacids – Uses & common additives Uses: Dyspepsia Symptomatic relief in peptic ulcer Gastro Esophageal Reflux Disease (GERD) with alginates Alginates - Form foamy layer on top of gastric contents & reduce reflux into esophagus. Simethicone - Decreases surface tension thereby reduces bubble formation - Added to reduce flatulence. Oxethazaine - Surface anaesthetic

taken hourly for severe symptom or uncontrolled reflux Administration taken hourly for severe symptom or uncontrolled reflux taken at least one and three hours after each meal and at bedtime for uncomplicated ulcer should be administered as suspension form (greater neutralization) tablet should be thoroughly chewed for maximum effect frt

Systemic (absorbable) antacids (NaHCO3) absorbed into blood stream -► alkalosis, sodium retention in renal insufficiency, precipitates hypertension (not recommended for long-term use) release CO2 -► belching, abdominal discomfort Non-systemic (unabsorbable) antacids not absorbed into blood stream -► no alkalosis All Mg2+ salts cause diarrhoea and Al(OH)3 and CaCO3 cause constipation frt

Magnesium trisilicate relatively poor neutralizing action, react slowly with acid to form silicon dioxide that adsorbs pepsin, forms gelatinous SiO2, which has demulcent action (coating on ulcer crater) and also useful for heartburn Mg (OH)2 has prompt action, long duration, cathartic with large doses is due to osmotic effect (also used as osmotic cathartic) frt

also useful for heartburn adsorbs & inactivates pepsin Al (OH)3 also useful for heartburn adsorbs & inactivates pepsin it also adsorbs phosphate in the intestine & are excreted in faeces, decreases blood phosphate and increase resorption from bone untoward effects of Al(OH)3 are constipation, phosphate deficiency, osteoporosis, osteodystrophy, encephalopathy, myopathy in renal disease frt

Drug Interactions with Antacids decrease absorption of tetracycline, ciprofloxacin due to chelation with Mg2+, Al3+ decrease the dissolution and absorption of ketoconazole due to decreased acidity interfere the action of sucralfate due to decreased acidity frt

I am prescribing Low carb diet for your diabetes High carb diet for your constipation Low fat diet for your heart disease High fat diet for your nerves And “one gallon of antacid daily for your stomach ulcer”

H2 receptor antagonists Competitive blockers of histamine at H2 receptors H2 antagonists are more effective in inhibiting nocturnal acid secretion (which depends largely on histamine) but have a modest effect on meal-stimulated acid secretion (by gastrin, ACh & histamine). Thus, they block more than 90% of nocturnal acid but only 60–80% of daytime acid secretion. Promote healing of duodenal & gastric ulcers prevent stress ulcers. Relapses are likely when the drugs are discontinued.

H2 recepter Antagonists frt 26

H2 receptor antagonists Cimetidine is an enzyme inhibitor (↑ses conc. of Warfarin, theophylline, phenytoin, ethanol) & no more used due to various side effects such as gynecomastia, galactorrhea (antiandrogenic & ↑ prolactin levels) Ranitidine is given twice a day or as a single nocturnal dose. Famotidine and nizatidine are given once a day. Other e.g. Roxatidine, Loxatidine

H2 receptor antagonists Uses: Peptic ulcer Reflux esophagitis Nonulcer dyspepsia ↓ bleeding in stress-related gastritis in seriously ill patients in ICU (administered iv either as intermittent injections or continuous infusions). ADR: Well tolerated with minimal ADR. diarrhea, rash, hypergastrinaemia, Headache, myalgia, bradycardia

- peptic ulcer (DU, GU, reflux oesophagitis) Uses: - peptic ulcer (DU, GU, reflux oesophagitis) - uncomplicated GERD - stress ulcer - Zollinger-Ellison syndrome - GI bleeding due to hepatic failure - preanaesthetic medication - systemic mastocytosis, basophilic leukaemia frt

Proton Pump Inhibitors frt 30

Proton Pump Inhibitors (PPIs) Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole Most effective in suppressing acid production as they act on the terminal step in the acid secretory pathway & irreversibly inhibit the proton pump (H+ K+ ATPase). Drugs of choice in peptic ulcer and have replaced H2 blockers to a large extent due to their safety and high efficacy. As they are acid labile, the prodrugs of PPI are given as enteric coated granules. PPI undergo activation in the parietal cells.

Avoid during pregnancy & lactation Act for more than 24 hrs (irreversible inhibition) & duration of action increases following continuous administration. Cause marked inhibition of basal & stimulated acid secretion & acid secretion resumes only after synthesis of new molecules. ADR: Extremely safe, well tolerated - Abdominal pain, GI upset, pain in joints, confusion etc. Avoid during pregnancy & lactation Causes hypergastrinemia – produces carcinoid tumor in rats (not reported in humans) frt

Enzyme inhibition may decrease the metabolism of drugs like warfarin, diazepam etc. Uses: efficacy is more if given in the morning before breakfast. Peptic ulcer Reflux esophagitis Component of H. pylori eradication regimens Zollinger-Ellison syndrome – hypersecretory state caused by a gastrin producing tumor

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Mucosal protective agents Also known as cytoprotectives, they enhance the mucosal protection mechanisms and or provide a physical barrier over the surface of the ulcer. Sucralfate Misoprostol Colloidal bismuth compounds (subcitrate) Carbenoxolone (ulcer healing)

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Sucralfate Sucralfate is a complex of aluminium hydroxide and sulfated sucrose & forms a viscous gel in acidic pH that adheres to ulcer base ses peptic activity ↑ses local PG synthesis, ↑ses mucous & bicarbonate secretion Given orally on empty stomach 1 hr before meals As it needs acid for activation, avoid concurrent acid suppressing agents. As effective as H2 blockers ADR: very few, constipation, dry mouth, nausea, vomiting,  ses absorption of other drugs (fluoroquinolones, digoxin etc.)

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Misoprostol NSAID produce gastric ulceration by Inhibition of PG production in the gastric mucosa. Misoprostol is a PGE1 analogue. Acts on parietal cell to reduce acid secretion Enhance mucosal blood flow, increases mucus & bicarbonate secretion Uses: with NSAID as prophylactic agent. ADR: Diarrhoea & abdominal cramps PPI are more effective & better tolerated Other e.g. Enprostil, Rioprostil

Colloidal bismuth compounds Coats ulcer base, adsorbs pepsin, increases local PG, stimulates mucus & bicarbonate secretion ↓ses peptic activity On H. pylori – bactericidal, prevents its adherence to gastric mucosa, inhibits bacterial enzymes. Use in H. pylori control regimens. ADR: Not used for long periods – bismuth toxicity, blacken stools & tongue Preparations: Colloidal bismuth subcitrate etc.

Carbenoxolone It is an ulcer protective obtained from a plant Increases production, secretion & viscosity of mucus which covers the ulcer area ADR limit its use Pirenzepine: Anticholinergic drug decreases acid production Status: not used due to availability of better drugs

Drug regimens to eradicate H. pylori Amoxicillin Clarithromycin Metronidazole Bismuth salts Acid suppressors H Pylori–Associated Ulcers For H pylori–associated ulcers, there are two therapeutic goals: heal the ulcer and eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH— lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 10–14 day regimen of "triple therapy": a proton pump inhibitor twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily. For patients who are allergic to penicillin, metronidazole 500 mg twice daily should be substituted for amoxicillin. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4–6 weeks to ensure complete ulcer healing. frt

DRUGS FOR ERADICATION OF H. pylori Triple therapy (1 week regimen) ACID SUPPRESSANTS ANTIBIOTICS E/L/O/P/R/Ranitidine + Amoxicillin + Clarithromycin L/O/Ranitidine + Amoxicillin + Metronidazole E/L/O/P/R/Ranitidine + Clarithromycin + Metronidazole frt

H. pylori eradication The most effective regimens for H pylori eradication are combinations of two antibiotics + PPI or H2 blocker for 2 weeks. Choose two AMA from: metronidazole – 500 mg x 2 /d clarithromycin – 250-500 mg x 2 /d amoxicillin – 1 g x 2 /d plus H2-blockers or PPI (twice a day) to ↓se acid secretion Acid suppressors to be continued for 4 – 6 weeks. frt

Treatment of Gastro-Esophageal Reflux disease (GERD) Antacids & antacid adjuncts H2 receptor blockers Prokinetic- metoclopramide, domperidone, cisapride Sucralfate PPIs

list the ulcer promoting and preventing factors. Objectives for Self study & Learning outcomes: The learner should be able to list the ulcer promoting and preventing factors. explain the applied physiology of acid secretion & the sites of drug action. classify drugs useful in peptic ulcer based on their mechanism of action with suitable examples. discuss the pharmacology of antacids, H2 receptor antagonists, proton pump inhibitors and mucosal protectives explain the basis of NSAIDs induced peptic ulcer and preventive measures mention regimens to eradicate H pylori.