Antacids and Antiulcer Agents 263 Table 7.3.1: Classification of drugs used in peptic ulcer I Drugs which reduce gastric acid secretion i H2-receptor antagonists Cimetidine (CIMETIN) 200-400 mg TDS-QID, 400 mg HS, 200-400 mg/day IM/IV 150 mg BD/HS, 50-100 mg/day IM/IV 40 mg HS, 20 mg BD 75-150 mg HS Ranitidine (HISTAC) Famotidine (FACID) Roxatidine (ZORPEX) Also available Nizatidine, Loxatidine ii Proton pump inhibitor Omeprazole (OMIZAC) 20-60 mg OD Pantoprazole (PANTOCID) 40 mg OD Rabeprazole (VELOZ) 20 mg OD Also available Esomeprazole, Lansoprazole iii Prostaglandin analogues Misoprostol (CYTOTEC) 200 µg QID Enprostil 35-140 µg/day Also available Rioprostil, Arbaprostil, Trimoprostil II Ulcer healing agents Carbenoxolone sodium (GASTRIULCER) 100 mg TDS III Ulcer protective agents Sucralfate (SUCRASE) g one hr before each (3) meals and at bed time IV Antacids (Neutralize gastric acid) Systemic antacids Sodium bicarbonate Nonsystemic antacids Magnesium carbonate Magnesium hydroxide (MILK OF MAGNESIA) Magnesium trisilicate Aluminium hydroxide gel (ALUDROX) Magaldrate (STACID) Calcium carbonate cardiac arrest due to histamine release The cimetidine has antiandrogenic action and can cause gynaecomastia, loss of libido and impotence, otherwise all other H2 blockers are devoid of these side effects Therapeutic Uses H2 blockers are used in the treatment of: • Duodenal ulcer • Gastric ulcer 0.3-1.5 g TDS-QID 0.5-2 g/day 0.3-1 g/day 0.5-1 g/day 0.5-1 g/day 400-800 mg/day 0.5-1 g/day • • • • Zollinger-Ellison syndrome (ZES) Gastroesophageal reflux NSAID’s induced ulcers Prophylaxis of aspiration pneumonia CIMETIDINE Low potency, short duration of action Oral bioavailability is 60% and 2/3 is excreted unchanged in urine and bile Incidence of adverse effects is 5% 264 It has poor CNS entry but in elderly and in patients with impaired renal functions, CNS symptoms may occur It displaces dihydrotestosterone from cytoplasmic receptors (antiandrogenic action) and inhibits estradiol degradation by liver High doses given for longer periods produce gynaecomastia, decreased libido and impotence It inhibits cytochrome P450 catalyzed hydroxylation of estradiol in men, also slowing metabolism of many drugs and concurrent administration of cimetidine will prolong the half life of many drugs (warfarin, phenytoin, theophylline, phenobarbital, benzodiazepines, propranolol, nifedipine, digitoxin, quinidine, mexiletine, tricyclic antidepressants) Section 7/ Drugs Acting on GIT ROXATIDINE Roxatidine inhibit H2 induced gastric secretion with a potency greater than cimetidine and in the same range as ranitidine Its acetate salt is more than 95% absorbed after oral administration and rapidly converted to roxatidine by esterases in small intestine and liver Plasma t½ is hours Peak plasma levels occur about hours after dosing Effects of the drug persist for about 12 hours It has use in prophylaxis of acid aspiration syndrome after induction of anaesthesia In a dose of 150 mg HS as premedication affords reliable protection against the consequences of acid aspiration until 11 AM the next day and decreases the danger of aspiration by reducing the high volumes of gastric juice RANITIDINE to times more potent than cimetidine Produces higher suppression of gastric acid and action lasts longer than cimetidine No clinically significant drug interaction and side effects are seen FAMOTIDINE On a weight basis 20 times more potent than cimetidine and 7.5 times more potent than ranitidine in inhibiting basal and pentagastrin stimulated gastric acid secretion It is a competitive-noncompetitive inhibitor of H2 receptors It has a longer duration of action Oral bioavailability is 40-50% and is excreted unchanged (70%) in urine Incidence of adverse effects is low It is more useful in ZE syndrome and prophylaxis of aspiration pneumonia PROTON PUMP INHIBITOR OMEPRAZOLE Omeprazole is gastric proton pump inhibitor which reduces gastric acid secretion It inhibits the enzyme H+K+ATPase in the parietal cells of gastric mucosa It effectively inhibits both basal and stimulated acid secretion irrespective of the stimulus It has quick onset of action and effective control of gastric acid secretion is achieved with once daily dosing It has no effect on pepsin, intrinsic factor, juice volume and gastric motility Proton pump inhibitors not exhibit anticholinergic or H2 receptor antagonistic properties Omeprazole distributes widely and is rapidly eliminated from plasma by metabolism in liver The antisecretory effect Antacids and Antiulcer Agents persists for much longer as it strongly binds to H+ K+ ATPase The disposition is not altered in patients with renal disease or in those undergoing haemodialysis Increased age and liver disease delays plasma clearance of the drug but this does not necessitate dosage adjustment in these patients It is indicated in: • • • • Treatment of duodenal ulcer Treatment of gastric ulcer Treatment of reflux oesophagitis For control of acid secretion in patients of Zollinger-Ellison syndrome It is well tolerated Nausea, headache, diarrhoea, constipation and flatulence have been reported occasionally, Rarely skin rash has occurred in few patients RABEPRAZOLE Rabeprazole belongs to substituted benzimidazole proton-pump inhibitors In gastric parietal cells, rabeprazole is protonated, accumulates and is transformed to an active sulfenamide Following oral administration of 20 mg, rabeprazole is absorbed and can be detected in plasma by one hour Rabeprazole is 96.3% bound to plasma proteins Rabeprazole is extensively metabolized The thioether and sulfone are the primary inactive metabolites 90% of the drug is eliminated in the urine, primarily as thioether carboxylic acid, its glucuronide and mercapturic acid metabolites It is indicated in erosive and ulcerative gastroesophageal reflux disease, healing of duodenal ulcers and Zollinger Ellison syndrome 265 Adverse effects include nausea, diarrhoea, skin eruptions, headache and dizziness Other proton pump inhibitors e.g., lansoprazole is more potent than omeprazole and has higher bioavailability, rapid onset of action and longer duration of action Pantoprazole is the new H+K+ATPase inhibitor with similar properties and action to omeprazole PROSTAGLANDIN ANALOGUES PGE2 and PGI2 are the main prostaglandins synthesized by gastric mucosa They decrease acid secretion and improve mucosal defense mechanism by: • Stimulation of synthesis and release of mucus • Enhance bicarbonate production • Enhancement of tight junctions of cell membrane architecture • Inhibit gastrin production • Stimulation of a number of cellular transport processes • Stimulation of DNA content in damaged gastric mucosa by a process termed as cytoprotection The important use of prostaglandin analogues is in the arthritic patients who are on chronic use of NSAID’s and are not responding to H2 receptor antagonists MISOPROSTOL 200 µg QID was of similar efficacy to cimetidine 300 mg TDS in healing duodenal and gastric ulcer Pain relief occurred more slowly than with cimetidine Shown to heal erosions, ulcers due to NSAIDs Section 7/ Drugs Acting on GIT 266 ENPROSTIL 35-140 µg day heal duodenal and gastric ulcer but are less effective than H2 receptor antagonists ULCER HEALING DRUGS CARBENOXOLONE SODIUM It is a steroid like triterpenoid synthetic derivative of glycyrrhizic acid (obtained from liquorice) and has been found to be effective in healing both gastric and duodenal ulcer without affecting volume or acidity of gastric juice It acts by increasing mucus production, slowing turnover of gastric cells and increasing regeneration of cells around ulcer It also enhances pyloric tone preventing bile reflux It retards PG’s degradation in gastric mucosa Its mineralocorticoid side effects lead to Na + and water retention and K + loss preclude its use on large scale electrostatic interaction of the drug with proteins at ulcer site It also binds to basic fibroblast growth factor preventing its degradation and thereby promotes healing It also protects from intracellular enzymes released from damaged cells It also helps in formation of new blood vessels (angiogenesis) and helps in cell division (mitogenic) Sucralfate also inhibits release of cytokines (immunomodulator) It also has antibacterial activity It precipitates surface proteins at ulcer base and act as a physical barrier, preventing acid, pepsin and bile from coming in contact with ulcer base It also augments gastric mucosal PG synthesis thereby enhancing protective action It has no acid neutralizing action It promotes healing of both gastric and duodenal ulcers and also prevents ulcer recurrence SUCRALFATE Topical sucralfate (4-10%) is also useful in management of decubitus ulcer, diabetic ulcers, chemical and thermal burns, radiation induced skin damage, vaginal ulceration, oral and genital ulceration It is a basic aluminium salt of sucrose octasulfate It polymerizes at pH < to form a sticky, viscid yellow white gel which adheres to ulcer base The gel acts as a strong mechanical barrier because of a strong Side effects include dry mouth, constipation, nausea, vomiting, rash, pruritus, dizziness It adsorbs and interferes with absorption of tetracycline, cimetidine, digoxin and phenytoin ULCER PROTECTIVE AGENTS Section Drugs Acting on Endocrine System ... Effects of the drug persist for about 12 hours It has use in prophylaxis of acid aspiration syndrome after induction of anaesthesia In a dose of 150 mg HS as premedication affords reliable protection... receptors (antiandrogenic action) and inhibits estradiol degradation by liver High doses given for longer periods produce gynaecomastia, decreased libido and impotence It inhibits cytochrome... from plasma by metabolism in liver The antisecretory effect Antacids and Antiulcer Agents persists for much longer as it strongly binds to H+ K+ ATPase The disposition is not altered in patients