DRUGS USED FOR PEPTIC DISORDER INCLUDING H.PYLORI INFECTION (PROTON PUMP INHIBITORS)

Transcription

1 DRUGS USED FOR PEPTIC DISORDER INCLUDING H.PYLORI INFECTION (PROTON PUMP INHIBITORS) LEARNING OBJECTIVES By the end of the lecture the student should be able to know: Treatments of peptic ulcer H2 receptor antagonists Proton pump inhibitors Triple & quadruple therapy INTRODUCTION 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. The etiology of peptic ulcer is not clearly known. It results probably due to an imbalance between the aggressive (acid, pepsin and H. pylori) and the defensive (Gastric mucus and bicarbonate secretion, prostaglandins, Nitric oxide, innate resistance of the mucosal cells) factors. INTRODUCTION The concept of balance between the aggressive capacities of the acid plus pepsin and the defensive mechanisms of the mucosa is a useful. An ulcer is thought to develop when the equilibrium is disturbed either by enhanced aggressiveness or by lessened mucosal resistance. DUODENAL ULCER On average, patients with duodenal ulcer produce about twice as much HCI as normal subjects, but there is much overlap, and about half the patients with duodenal ulcer have acid outputs in the normal range. Patients with gastric ulcer produce normal or reduced amounts of acid.

2 PROTECTIVE FACTORS The factors that protect the mucosa comprise its: Impermeability to H + ion (the mucosal barrier to H + ). Ability to secrete mucus and bicarbonate ion. Blood flow and its capacity rapidly to replace damaged epithelial cells. Endogenous prostaglandins are probably involved in all these mechanisms. RISK FACTORS Use of non-steroidal anti-inflammatory drugs, cigarette smoking, the presence of helicobacter pylori in the stomach and heredity (male sex, blood group O) Influence that equilibrium unfavorably and are associated with increased incidence of peptic ulcer. APPROACHES FOR THE TREATMENT OF PEPTIC ULCER Reduction of gastric acid secretion: (a) H 2 antihistamines: Cimetidine, Ranitidine, Famotidine, Roxatidine, Loxatidine. (b) Proton pump inhibitor: Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole. (c) Anticholinergics: Pirenzepine, Propantheline, Oxyphenonium.

3 (d) Prostaglandin analogues: Misoprostol, Enprostil, Rioprostil. 2. Neutralization of Gastric Acid (Antacids) (a) Systemic: Sodium bicarbonate, Sodium Citrate. (b) Non-systemic: Magnesium hydroxide, Mag. trisilicate, Aluminium hydroxide gel, Magaldrate, Calcium Carbonate. 3. Ulcer protectives: Sucralfate, Colloidal bismuth subcitrate (CBS) 4. Ulcer healing drugs: Carbenoxolone sodium 5. Anti- H. pylori drugs: Amoxicillin, Clarithromycin, Metronidazole, Tinidazole, Tetracycline.

4 H 2 RECEPTOR ANTAGONISTS Cimetidine was the first H 2 blocker to be introduced clinically and is described as the prototype. Cimetidine is clinically indicated for: the treatment of active gastric and duodenal ulcer, prevention of duodenal ulcer recurrence, CIMETIDINE Treatment of gastric acid hyper-secretory states (gastrinoma, Zollinger- Ellison syndrome) Other conditions related to the secretion of gastric acid, like gastroesophageal reflux disease and Stress-related mucosal damage (Ulcers, bleeding). INHIBITORS OF THE H + /K + -ATPASE PROTON PUMP Omeprazole is the first of a class of drugs that bind to the H + /K + - ATPase enzyme system (proton pump) of the parietal cell, thereby suppressing secretion of hydrogen ions into the gastric lumen. The membrane-bound proton pump is the final step in the secretion of gastric acid. Four additional PPls are now available: lansoprazole, rabeprazole, pantoprazole and esomeprazole.

5 PPI Actions: All of these agents are prodrugs with an acid- resistant enteric coating to protect them from premature activation by gastric acid. The coating is removed in the alkaline duodenum, and The prodrug, a weak base, is absorbed and transported to the parietal cell canaliculus. PPI There, it is converted to the active form, which reacts with a cysteine residue of the H + /K + -ATPase, forming a stable covalent bond. It takes about 18 hours for the enzyme to be resynthesized. At standard doses, all PPls inhibit both basal and stimulated gastric acid secretion more than 90%. Acid suppression begins within 1-2 hours after the first dose of lansoprazole and slightly earlier with omeprazole. PHARMACOKINETICS - PPI Oral forms are prepared as acid resistant formulations that release the drug in the intestine (because they are degraded in acid media) After absorption, they are distributed by blood to parietal cell canaliculi They irreversibly inactivate the proton pump molecule but half life is very short and only 1-2 hours PHARMACOKINETICS - PPI Still action persists for hours after a single dose irreversible inhibition of PPI and new PP synthesis takes time (24 to 48 hour suppression of acid secretion, despite the much shorter plasma halflives of the parent compounds) Plateau state is attained after 4-5 days of dosing Action lasts for 4-5 days even after stoppage of the drug

6 PHARMACOKINETICS - PPI Given on an empty stomach because food affects absorption They should be given 30 minutes to 1 hour before food intake because an acidic ph in the parietal cell acid canaliculi is required for drug activation, and food stimulates acid production Concomitant use of other anti-secretory drugs - H2 receptor antagonists reduces action Highly protein bound and rapidly Metabolized by the liver by CYP2C19 and CYP3A4 dose reduction necessary in severe hepatic failure Excreted in Kidneys minimally (no dose reduction needed in renal failure and elderly) ADVERSE EFFECTS The most common are: GIT troubles in the form of nausea, abdominal pain, constipation, flatulence, and Diarrhea Subacute myopathy, arthralgias, headaches, and skin rashes

7 ADVERSE EFFECTS Prolonged use: Gynaecomastia, erectile dysfunction Leucopenia and hepatic dysfunction Vitamin B12 deficiency Hyper-gastrinemia which may predispose to rebound hyper secretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors ) DRUG INTERACTION Inhibits metabolism of Warfarin Diazepam THERAPEUTIC USES Gastro-esophageal reflux disease (GERD) Peptic Ulcer - Gastric and duodenal ulcers Bleeding peptic Ulcer Zollinger-Ellison Syndrome Prevention of recurrence of non-steroidal anti-inflammatory 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

8 PPI DOSAGE SCHEDULE Omeprazole 20 mg OD. Lansoprazole 30 mg OD. Pantoprazole 40 mg OD. Rabeprazole 20 mg OD. Esomeprazole mg OD. TRIPLE THERAPY The BEST among all the Triple therapy regimen is Omeprazole / Lansoprazole Clarithromycin Amoxycillin / Metronidazole - 20 / 30 mg b.d mg b.d - 1gm / 500 mg b.d Given for 14 days followed by P.P.I for 4 6 weeks Short regimens for 7 10 days not very effective Some other Triple Therapy Regimens are Bismuth subsalicylate 2 tab qid Metronidazole Tetracycline mg qid mg qid

9 Ranitidine Bismuth citrate mg b.d Tetracycline mg b.d Clarithromycin / Metronidazole mg bd QUADRUPLE THERAPY Given when Triple Therapy fails Omeprazole / Lansoprazole - 20 / 30 mg bd Bismuth subsalicylate Metronidazole Tetracycline - 2 tabs qid mg qid mg qid Drugs causing peptic ulcer Non Steroidal Anti Inflammatory Drugs (NSAIDs) Glucocorticoids Cytotoxic agents