Antiulcer converted
- 1. :By: Ankit sharmA M.Pharma (Pharmacology) Bhupal Nobles University Udaipur, Rajasthan
- 2. PEPTIC ULCER Peptic ulcer occurs in that part of the gastrointestinal tract (g.i.t.) which is exposed to gastric acid and pepsin, i.e. the stomach and duodenum. A variety of psychosomatic, humoral and vascular derangements have been implicated and the importance of Helicobacter pylori infection as a contributor to ulcer formation and recurrence has been recognized. In gastric ulcer, generally acid secretion is normal or low, while deficient mucosal defence (mostly impaired mucus and bicarbonate secretion) plays a greater role. In duodenal ulcer, acid secretion is high in about half of the patients but normal in the rest.
- 3. 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.
- 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 own receptors located on the basolateral membrane of these cells. 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 Ca2+. The cAMP mediated proton pump activation also involves Ca2+. Gastrin is secreted from the antrum in response to rise in antral pH, food constituents and vagally mediated reflexes involving ganglion cells of the enteric nervous system (ENS).
- 5. Drugs for Peptic Ulcer
- 6. H2 ANTAGONISTS (Cimetidine) Four H2 antagonists cimetidine, ranitidine, famotidine and roxatidine are available in India; many others are marketed elsewhere. Cimetidine is adequately absorbed orally, though bioavailability is 60–80% due to first pass hepatic metabolism. Absorption is not interfered by presence of food in stomach. It crosses placenta and reaches milk, but penetration in brain is poor because of its hydrophilic nature. About 2/3 of a dose is excreted unchanged in urine and bile, the rest as oxidized metabolites. The elimination t½ is 2–3 hr.
- 7. H2 ANTAGONISTS (Cimetidine): Interactions Cimetidine inhibits several cytochrome P-450 isoenzymes and reduces hepatic blood flow. It inhibits the metabolism of many drugs so that they can accumulate to toxic levels, e.g. theophylline, phenytoin, carbamazepine, phenobarbitone, sulfonylureas, metronidazole, warfarin, imipramine, lidocaine, nifedipine, quinidine. Metabolism of propranolol and diazepam is also retarded, but this may not be clinically significant. Antacids reduce absorption of all H2 blockers. When used concurrently a gap of 2 hr should be allowed. Ketoconazole absorption is decreased by H2 blockers due to reduced gastric acidity.
- 8. Uses of H2 blockers Duodenal ulcer Gastric ulcer Stress ulcers and gastritis Zollinger-Ellison syndrome: It is a gastric hypersecretory state due to a rare tumour secreting gastrin. H2 blockers in high doses control hyperacidity and symptoms in many patients, but PPIs are the drugs of choice. Definitive treatment is surgical. Gastroesophageal reflux disease (GERD) Prophylaxis of aspiration pneumonia Urticaria
- 9. PROTON PUMP INHIBITORS : Omeprazole It is the prototype member of substituted benzimidazoles which inhibit the final common step in gastric acid secretion. All PPIs are administered orally in enteric coated (e.c.) form to protect them from molecular transformation in the acidic gastric juice. Oral bioavailability of omeprazole is ~50% due to acid lability. Bioavailability of all PPIs is reduced by food; they should be taken in empty stomach, followed 1 hour later by a meal to activate the H+K+ ATPase and make it more susceptible to the PPI.
- 10. PROTON PUMP INHIBITORS : Omeprazole Interactions Omeprazole inhibits oxidation of certain drugs: diazepam, phenytoin and warfarin levels may be increased. It interferes with activation of clopidogrel by inhibiting CYP2C19. Reduced gastric acidity decreases absorption of ketoconazole and iron salts. Clarithromycin inhibits omeprazole metabolism and increases its plasma concentration. Adverse effects PPIs produce minimal adverse effects. Nausea, loose stools, headache, abdominal pain, muscle and joint pain, dizziness are complained by 3–5%. Rashes (1.5% incidence), leucopenia and hepatic dysfunction are infrequent. On prolonged treatment atrophic gastritis has been reported occasionally.
- 11. ANTACIDS Antacids do not decrease acid production; rather, agents that raise the antral pH to > 4 evoke reflex gastrin release → more acid is secreted, especially in patients with hyperacidity and duodenal ulcer; “acid rebound” occurs and gastric motility is increased. The potency of an antacid is generally expressed in terms of its acid neutralizing capacity (ANC), which is defined as number of mEq of 1N HCl that are brought to pH 3.5 in 15 min (or 60 min in some tests) by a unit dose of the antacid preparation.
- 12. ANTACIDS Systemic Antacids Nonsystemic Antacids Sodium bicarbonate It is water soluble, acts instantaneously, but the duration of action is short. It is a potent neutralizer (1 g → 12 mEq HCl), pH may rise above 7. However, it has several demerits: (a) Absorbed systemically: large doses will induce alkalosis. (b) Produces CO2 in stomach → distention, discomfort, belching, risk of ulcer perforation. (c) Acid rebound occurs, but is usually short lasting. (d) Increases Na+ load: may worsen edema and CHF. Use of sod. bicarbonate is restricted to casual treatment of heartburn. It provides quick symptomatic relief. Other uses are to alkalinize urine and to treat acidosis. These are insoluble and poorly absorbed basic compounds; React in stomach to form the corresponding chloride salt. The chloride salt again reacts with the intestinal bicarbonate so that HCO3 ¯ is not spared for absorption—no acid-base disturbance occurs. However, small amounts that are absorbed have the same alkalinizing effect as NaHCO3.
- 13. Antacid combinations (a) Fast (Mag. hydrox.) and slow (Alum. hydrox.) acting components yield prompt as well as sustained effect. (b) Mag. salts are laxative, while alum. salts are constipating: combination may annul each other’s action and bowel movement may be least affected. (c) Gastric emptying is least affected; while alum. salts tend to delay it, mag./cal. salts tend to hasten it. (d) Dose of individual components is reduced; systemic toxicity (dependent on fractional absorption) is minimized.
- 14. Drug interactions of Antacids By raising gastric pH and by forming complexes, the non-absorbable antacids decrease the absorption of many drugs, especially tetracyclines, iron salts, fluoroquinolones, ketoconazole, H2 blockers, diazepam, phenothiazines, indomethacin, phenytoin, isoniazid, ethambutol and nitrofurantoin. Stagger their administration by 2 hours. The efficacy of nitrofurantoin is also reduced by alkalinization of urine.
- 15. ANTI-HELICOBACTER PYLORI DRUGS The US-FDA approved regimen is: Lansoprazole 30 mg + Amoxicillin 1000 mg+ clarithromycin 500 mg, all given twice daily for 2 weeks. The National Formulary of India (NFI, 2010) suggests a model H. pylori eradication regimen of 1 week consisting of: Omeprazole 40 mg OD + Metronidazole 400 mg TDS + Amoxicillin 500 mg TDS. 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.
- 16. Case Study A 45-year-old male patient presents with dyspepsia and dull epigastric pain which has been worsening gradually over the last one month. The pain is partly relieved by food, but becomes worse after 2 hours or so. Heart burn and pain which awakens him is often felt at night. Epigastric tenderness is detected on palpation. Upper gastrointestinal endoscopy reveals an ulcer measuring 12 mm X 18 mm in the 1st part of duodenum. His medical records show that he suffered similar episode of pain about 9 months ago. No endoscopy was done, but he was treated with omeprazole 20 mg OD for 6 weeks. Subsequently, nearly 3 months back, he suffered from loose motions and abdominal pain which was treated with a 5 day course of metronidazole + norfloxacin. Facility for H. pylori testing is not available. There is no history of NSAID use. What would be the most appropriate treatment option for him to achieve fast symptom relief, ulcer healing and prevention of further recurrences?
- 17. Solution This patient is suffering from recurrent peptic ulcer disease. The earlier episode of similar symptoms had responded to proton pump inhibitor (PPI) therapy. Therefore, it was also due to peptic ulcer. Symptom relief and ulcer healing can be achieved this time as well with the use of a PPI given for 4–8 weeks depending on endoscopic confirmation of ulcer healing. However, it alone cannot prevent recurrences, which most commonly are caused by persistent colonization of upper gastrointestinal tract by H. pylori. Since the same cannot be confirmed in the absence of testing facility, he should be given the benefit of H. pylori eradication therapy which largely prevents ulcer recurrences. A 3 drug, 2 week regimen would be the most effective option. Since he has a history of metronidazole use in the recent past, chances of nitroimidazole resistance are high, and he should be treated with a PPI (omeprazole 20 mg/lansoprazole 30 mg/pantoprazole 40 mg/rabeprazole 20 mg) + amoxicillin 750 mg + clarithromycin 500 mg, all given twice daily. The PPI should then be continued till endoscopic confirmation of healing is obtained, because the ulcer was larger than 10 mm in diameter.