Anti Ulcer drugs pharmacology and classification

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1. Drugs for Peptic ulcer

2. Peptic ulcer A peptic ulcer disease or PUD is an ulcer defined as mucosal erosions equal to or greater than 0.5 cm of an area of the gastrointestinal tract exposed to the acid and pepsin secretion. Stomach Lining Basics

3. Gastric Gland

4. Regulation of gastric acid secretion The terminal enzyme H + K + ATPase (proton pump) which secretes H + ions in the apical canaliculi of parietal cells can be activated by histamine, ACh and gastrin acting via their receptors located on the basolateral membrane of these cells. H istamine acting through H 2 receptors ACh acts partly directly and to a greater extent indirectly by releasing histamine from paracrine enterochromaffin-like (ECL) cells called “ histaminocytes ” located in the oxyntic glands. Gastrin is secreted from the antrum in response to a rise in antral pH, food constituents, especially peptides, and vagally mediated reflexes involving ganglion cells of the enteric nervous system (ENS).

5. H2 receptors activate H + K + ATPase by generating cAMP , muscarinic and gastrin/ cholecystokinin (CCK2) receptors appear to function through the phospholipase C → IP3–DAG pathway that mobilizes intracellular Ca 2+ The secretomotor response to gastrin and cholinergic agonists is expressed fully only in the presence of cAMP generated by H 2 activation . Histamine participates in the acid response to gastrin and ACh at more than one level, and H 2 antagonists suppress not only histamine but also ACh , pentagastrin and any gastric acid secretory stimulus. Prostaglandins have been ascribed a “ cytoprotective” role in the gastric mucosa by augmenting mucus and bicarbonate secretion from gastric mucosal epithelial cells as well as other actions.

6. The gastric mucus transforms into an adherent gell -like film over the mucosa which traps the secreted HCO 3 ¯ ions and prevents their neutralization by creating a barrier for the H+ ions in the juice and also shields the mucosa from attack by pepsin. PGE2 produced by gastric mucosa, inhibits acid secretion by opposing cAMP generation (in parietal cells) and gastrin release (from antral G cells). The secretion of the parietal cells is an isotonic solution of HCl (150 mmol/l) with a pH < 1, about 2.5 litres of gastric juice daily The concentration of hydrogen ions is more than a million times higher than that of the plasma.

7. The Cl - is actively transported into canaliculi in the cells that communicate with the lumen of the gastric glands and thus with the stomach itself. This Cl - secretion is accompanied by K + , which is then exchanged for H + from within the cell by a K + /H + ATPase + and bicarbonate ions . The latter exchanges across the basal membrane of the parietal cell for Cl - . at of the plasma.

8. Secretion of HCl by gastric parietal cell and its regulation C.Ase .—Carbonic anhydrase; Hist.—Histamine; ACh .—Acetylcholine; CCK2—Gastrin cholecystokinin receptor; M.— Muscarinic receptor; N—Nicotinic receptor; H2—Histamine H2 receptor; EP3—Prostaglandin receptor; ENS—Enteric nervous system; ECL cell—Enterochromaffin-like cell; GRP—Gastrin releasing peptide; + Stimulation; – Inhibition

9. The goals of antiulcer therapy are: Relief of pain Ulcer healing Prevention of complications (bleeding, perforation) Prevention of relapse. Gastritis is the precursor to PUD and it is clinically difficult to differentiate the two Stomach (called gastric ulcer) Duodenum (called duodenal ulcer) Esophagus (called Esophageal ulcer) Meckel's Diverticulum (called Meckel's Diverticulum ulcer)

10. Duodenal Vs Gastric Ulcers D u oden al Age: 25-75 years Gnawing or burning upper abdomen pain relieved by food but reappears 1-3 hrs after meals Worsening pain when stomach empty Bleeding occurs with deep erosion Haematemesis Maelena Ga s t r ic Age: 55-65 years Relieved by food but pain may persist even after eating Anorexia, wt loss, vomiting Infrequent or absent remissions Small % become cancerous Severe ulcers may erode (Slowly) through the stomach wall weight

11. Common and is a GIT motility disorder The most common factor is Acid content reflux back into the oesophagus Intense burning, sometimes belching Can lead to esophagitis, oesophagal ulcers, and strictures Commonly associated with obesity Improves with lifestyle management oesophagus Gastroesophageal Reflux Disease (GERD)

12. Imbalance primarily between Aggressive factors and Defensive factors Why Peptic ulcer occurs

13. What may contribute to imbalance ? Helicobacter pylori NSAIDs Ethanol Tobacco Severe physiologic stress (Burns, CNS trauma, Surgery, Severe medical illness) Steroids

14. Gram (-) rod with flagella H pylori is the most common cause of PUD Transmission route faecal-oral Secretes urease → convert urea to ammonia Produces an alkaline environment enabling survival in the stomach Almost all duodenal and 2/3 gastric ulcer patients are infected with HP Considered class 1 carcinogen → gastric cancer faecal-oral faecal-oral H. pylori

15. H 2 antagonists- These are the first class of highly effective drugs for acid-peptic disease but have now been surpassed by proton pump inhibitors. H 2 blockers are competitive antagonists of histamine at the H 2 receptors , but with famotidine, the antagonism is partly noncompetitive due to stronger binding to the H 2 receptors. These drugs block, histamine-induced gastric secretion, cardiac stimulation uterine relaxation and bronchial relaxation Human bronchial muscles express both contractile H 1 and relaxant H 2 receptors. Normally the H 1 response predominates, but H 2 mediated relaxation can be demonstrated after H 1 blockade. As such , H 2 blockers can potentiate histamine-induced bronchospasm. H 2 blockers attenuate fall in BP due to histamine, This is due to the blockade of relaxant H 2 receptors located directly on vascular smooth muscle.

16. Gastric secretion The action of H 2 blockers is marked inhibition of gastric secretion . All phases (basal, psychic, neurogenic, gastric) of secretion are suppressed dose-dependently , but the basal nocturnal acid secretion is suppressed more completely. Secretory response to not only histamine but all other stimuli ( ACh , gastrin, insulin, alcohol, food) is attenuated. The volume of gastric juice, pepsin content and intrinsic factor secretion are all reduced , but the most marked effect is on acid secretion. The usual ulcer healing doses produce 60–70% inhibition of 24-hour acid output. Gastric ulceration due to stress and drugs (NSAIDs, cholinergic, histaminergic) is prevented H 2 blockers have no direct effect on gastric or oesophagal motility or lower oesophagal sphincter (LES) tone .

17. Pharmacokinetics After oral administration, the H 2 antagonists distribute widely throughout the body (including into breast milk and across the placenta) and are excreted mainly in urine. Cimetidine , ranitidine, and famotidine are also available in intravenous formulations. The half-life of all of these agents may be increased in patients with renal dysfunction, and dosage adjustments are needed.

18. Comparison of H 2 antagonists Cimetidine Ranitidine Famotidine Nizatidine Bioavailability 80 50 40 >90 Relative Potency 1 5 -10 32 5 -10 Half life (hrs) 2 - 3 2 - 3 2.5 – 3.5 1.1 -1.6 DOA (hrs) 6 8 12 8 Inhibition o f CYP 450 1 0.1 Dose mg (bd) 400 150 20 150

19. H 2 antagonists - Uses Promote the healing of gastric and duodenal ulcers Duodenal ulcer – 70 to 90% at 8 weeks Gastric Ulcer – 50 to 75% NSAID ulcers induced ulcers Stress ulcer and gastritis GERD in mild cases Zollinger-Ellison syndrome Prophylaxis of aspiration pneumonia

20. Headache, dizziness, bowel upset, dry mouth CNS: Confusion, restlessness Bolus IV – release histamine – bradycardia, arrhythmia, cardiac arrest Cimetidine has antiandrogenic actions Increases plasma prolactin and inhibits degradation of estradiol by liver High doses given for long periods have produced gynaecomastia, loss of libido, impotence and short-lasting decrease in sperm count . Adverse effects

21. Drug interactions Cimetidine inhibits several CYP-450 isoenzymes and reduces hepatic blood flow, so inhibits metabolism of many drugs like theophylline, metronidazole, phenytoin, imipramine etc . Antacids reduce the absorption of all H2 blockers

22. PROTON PUMP INHIBITORS (PPIs) The membrane-bound proton pump is the final step in the secretion of gastric acid. The PPIs bind to the H+/K+-ATPase enzyme system (proton pump) and suppress the secretion of hydrogen ions into the gastric lumen . The available PPIs include dexlansoprazole , esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. Omeprazole, esomeprazole, and lansoprazole are available over-the counter for short-term treatment of GERD .

23. Omeprazole It is the prototype member of substituted benzimidazoles which inhibit the final common step in gastric acid secretion. MOA - Omeprazole is inactive at neutral pH, but at pH < 5 it rearranges to two charged cationic forms ( a sulphenic acid and a sulphenamide configurations ) that react covalently with SH groups of the H+K+ATPase enzyme and inactivate it irreversibly. When two molecules of omeprazole react with one molecule of the enzyme . After absorption into bloodstream and subsequent diffusion into the parietal cell, it gets concentrated in the acidic canaliculi because the charged forms generated at the acidic pH are unable to diffuse back.

24. It gets tightly bound to the enzyme by covalent bonds . These features and the specific localization of H+K+ATPase to the apical membrane of the parietal cells confer high degree of selectivity of action to omeprazole and all other PPIs . Acid secretion resumes only when new H+K+ATPase molecules are synthesized (reactivation half time 18 hours). It also inhibits gastric mucosal carbonic anhydrase PP I – c on td.

25. Pharmacokinetics All PPIs are administered orally in enteric-coated ( e.c. ) form to protect them from the molecular transformation in the acidic gastric juice. PPIs should be taken 30 to 60 minutes before breakfast or the largest meal of the day . Esomeprazole, lansoprazole, and pantoprazole are also available in intravenous formulations. The plasma half-life of these agents is only a few hours, they have a long duration of action due to covalent bonding with the H+/K+- ATPase enzyme. Omeprazole is a high plasma protein bound, rapidly metabolized in the liver by CYP2C19 and CYP3A4 Metabolites of these agents are excreted in urine and faeces .

26. Drugs Bioavailability Half Life ( hr) Dose (mg) BD Omeprazole 40-65 % 0.5-1 20 Esomeprazole 50-89 % 1.2 20-40 Lansoprazole 80-90 % 1.5 30 Pantoprazole 77 % 1.9 40 Rabeprazole 52 % 0.7-2.0 20 Pharmacokinetics of different PPIs

27. PP I – c on td. Therapeutic uses: Gastroesophageal reflux disease (GERD) Peptic Ulcer - Gastric and duodenal ulcers Bleeding peptic Ulcer Stress ulcers Zollinger Ellison Syndrome Prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID) - associated gastric ulcers in patients who continue NSAID use. Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections Aspiration Pneumonia

28. Adverse Effects Nausea, loose stools, headache abdominal pain, constipation, Muscle & joint pain, dizziness, rashes Rare Gynaecomastia, erectile dysfunction Leucopenia and hepatic dysfunction Osteoporosis in elderly on prolonged use

29. Drug interactions Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and cyclosporine. It interferes with activation of clopidogrel by inhibiting CYP2C19 . Reduced gastric acidity decreases absorption of ketoconazole and iron salts. However, drug interactions are not a problem with the other PPIs.

30. Muscarinic antagonists Block the M 1 class receptors Reduce acid production, Abolish gastrointestinal spasm Pirenzepine and Telenzepine Reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia Unpopular as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision) meal-stimulated

31. Prostaglandin analogues- Misoprostol Inhibit gastric acid secretion Enhance local production of mucus or bicarbonate Help to maintain mucosal blood Therapeutic use: Prevention of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)

32. M i s opr o stol Doses: 200 mcg 4 times a day ADRs: Diarrhoea and abdominal cramps Uterine bleeding Abortion Contraindications: Inflammatory bowel disease Pregnancy (may cause abortion)

33. Antacids Weak bases that neutralize acid Also inhibit formation of pepsin (As pepsinogen converted to pepsin at acidic pH) Acid Neutralizing Capacity: Potency of Antacids e xpressed in terms of Number of mEq of 1N HCl that are brought down to pH 3.5 in 15 minutes by a unit dose of the preparation (1 gm)

34. Systemic antacids Sodium Bicarbonate: Potent neutralizing capacity and acts instantly ANC: 1 gm = 12 mEq DEMERITS: Systemic alkalosis Distension, discomfort and belching – CO2 Rebound acidity Sodium overload

35. Non systemic Antacids Magnesium hydroxide (ANC 30 mEq) Aqueos suspension is called Milk of magnesia Magnesium trisilicate (ANC 10 mEq) Aluminium Hydroxide (ANC 1-2.5mEq/g) Magaldrate – hydrated hydroxy magnesium aluminate

36. Non systemic antacids Insoluble and poorly absorbed basic compounds React in stomach to form corresponding chloride salt The chloride salt again reacts with the intestinal HCO3 - so that HCO3 - is not spared for absorption .

37. Chemical reactions of antacids with HCl in the stomach

38. Non systemic antacids Duration of action : 30 min when taken in empty stomach and 2 hrs when taken after a meal Adverse effects: Aluminium antacids – constipation Mg2+ antacids – Osmotic diarrhoea In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy Fast (Mag. hydroxy) and slow (Alum. hydroxy) acting components yield prompt as well as sustained effects . Mag. salts are laxative, while alum. Salts are constipating : combination may annul each other’s action and bowel movement may be least affected. Gastric emptying is least affected; while alum. salts tend to delay it, mag./cal. Salts tend to hasten it. The dose of individual components is reduced ; systemic toxicity (dependent on fractional absorption) is minimized.

39. DIGENE: Dried alum. hydrox . gel 300 mg, mag. alum. silicate 50 mg, mag. hydrox . 25 mg, methylpolysilox . 10 mg per tab. DIGENE GEL: Mag. hydrox . 185 mg, alum. hydrox . gel 830 mg, sod. carboxymethyl cellulose 100 mg, methylpolysilox . 25 mg per 10 ml susp. GELUSIL: Dried alum. hydrox . gel 250 mg, mag. trisilicate 500 mg per tab. GELUSIL LIQUID: Mag. trisilicate 625 mg, alum. hydrox . gel 312 mg per 5 ml susp. MUCAINE: Alum. hydrox . 290 mg, mag. hydrox . 98 mg, oxethazaine 10 mg per 5 ml susp.

40. Drug interactions By raising gastric pH & forming insoluble complexes ↓ absorption of many drugs Tetracyclines, iron salts, H 2 Blockers, diazepam, phenytoin, isoniazid, ethambutol

41. S u cralfat e – u lcer protective Aluminium salt of sulfated sucrose MOA : In acidic environment ( pH <4) it polymerises by cross-linking molecules to form a sticky viscous gel that adheres to the ulcer crater - more on duodenal ulcer Astringent action and acts as a physical barrier Dietary proteins get deposited on this layer forming another coat

42. S u cralf a te – c o nt d . Concurrent antacids avoided , (as it needs acid for activation) Uses: Prophylaxis of Stress ulcers Bile reflux gastritis Topically – burn, bedsore ulcers, excoriated skins Dose : 1 gm one Hr before 3 major meals and at bedtime for 4-8 weeks ADRs : Constipation, hypophosphatemia Drug interactions : A dsorbs many drugs and interferes with their absorption

43. Colloidal Bismuth Subcitrate (CBS) Mechanism of action CBS and mucous form glycoprotein bi complex which coats ulcer crater ↑ secretion of mucous and bicarbonate through stimulation of mucosal PGE production Detaches H.pylori from the surface of the mucosa and directly kills them

44. Colloidal Bismuth subcitrate Dose: 120 mg 4 times a day Adverse effects blackening of tongue, stools, dentures Prolonged use may cause osteodystrophy and encephalopathy Diarrhoea, headache, dizziness

45. Eradication of H.pylori N o a c i d N o u l ce r OLD TESTAMENT No HP No ulcer NEW TESTAMENT

46. H. pylori Gram (-) rod Associated with gastritis, gastric & duodenal ulcers, gastric adenocarcinoma Transmission route fecal-oral Secretes urease → convert urea to ammonia Produces an alkaline environment enabling survival in stomach

47. Triple Therapy 1. Omeprazole / Lansoprazole - 20 / 30 mg bd 2. Clarithromycin - 250 mg or 500 mg bd 3. Amoxycillin / Metronidazole - 1gm , 500 mg/400mg tds One week regimens(mg)

48. Other 2 weeks regimen(mg) Amoxicillin 750 + Tinidazole 500 + O meprazole 20 mg/ lansoprazole 30 mg BD C larithromycin 250 + Tinidazole 500/amoxicillin 1000 + lansoprazole 30 mg BD

49. For large ulcers (> 10 mm in diameter) or those complicated by bleeding/perforation, the PPI should be continued beyond the 2-week triple-drug regimen till complete healing occurs. Quadruple therapy with CBS 120 mg QID + tetracycline 500 mg QID + metronidazole 400 mg TDS + omeprazole 20 mg BD is advocated for eradication failure cases. Another quadruple therapy regimen with PPI + amoxicillin + clarithromycin + metronidazole all twice daily for 2 weeks has been tested in Europe with a>90% eradication rate. All regimens are complex and expensive, side effects are frequent and compliance is poor. Higher failure rates (20–40%) have been reported from India. Also, the 5-year recurrence rate of H. pylori infection is higher . long-term benefits of anti-H. pylori therapy includes lowering ulcer disease prevalence and prevention of gastric carcinoma/lymphoma

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