Drugs in Peptic Ulcer Disease and GERD. R. A. Nimmi Dilsha Department of Pharmacy Faculty of Health Sciences The Open University of Sri Lanka
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1 Drugs in Peptic Ulcer Disease and GERD R. A. Nimmi Dilsha Department of Pharmacy Faculty of Health Sciences The Open University of Sri Lanka
2 Peptic ulcer Imbalance between The damaging effects of gastric acid and pepsin And the defense mechanism that protect the gastric and duodenal mucosa from these substances
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4 Peptic ulcer Protective Aggresive Prostaglandis Mucus Bicarbonates Mucosal blood flow Acid Pepsin NSAIDs Helicobactor pylori
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6 Acid secretion by stomach
7 Peptic ulcer
8 DRUGS IN PEPTIC ULCER DISEASE Drugs are used to Neutralize gastric acid Inhibit gastric acid secretion Enhance mucosal resistance Eradicate Helicobactor pylori infecion
9 NEUTRALISATION OF GASTRIC ACID ANTACIDS Antacids are basic substances that reduce gastric acidity by neutralizing hydrochloric acid Bases:hydroxide, trisilicate, carbonate and bicarbonate Metalic ion: aluminium, magnesium or sodium
10 NEUTRALISATION OF GASTRIC ACID ANTACIDS Mechanism Neutralize gastric acidity Inactivate pepsin Pepsin is inactive at PH>5 Further inactivated by aluminum and magnesium Uses Relieve dyspeptic sympotms Ulcer dyspepsia Non erosive gastro-esophageal reflux
11 NEUTRALISATION OF GASTRIC ACID ANTACIDS Aluminium and Magnesium containing antacids (aluminium hydroxide, magnesium carbonate/hydroxide/trisilicate) Relatively insoluble in water Long acting if retained on stomach Mg laxative Al - constipating If contain both reduced colonic effects
12 NEUTRALISATION OF GASTRIC ACID Sodium bicarbonate No longer prescribed alone in dyspepsia Added to mixtures(quick effect) Simeticone Added to antacid mixtures as an antifoaming agent to relieve flatulence Alginates Combined with antacids to encourage adherence of the mixture to the mucosa
13 NEUTRALISATION OF GASTRIC ACID ANTACIDS Antacids should preferably not taken at the same time as other drugs since they may impair absorption Can damage the enteric coatings
14 H2 Receptor antagonists Bind selectively and competitively to H2 receptors at the basolateral membrane of the gastric parietal cells Also reduce acetylcholine induced and gastrin induced acid secretion Tolerance can occur due to receptor down regulation H2 receptors antagonists a α suppression of nocturnal acid secretion Single evening dose/8 weeks
15 H2 Receptor antagonists Cimetidine,ranitidine,famotidine,nizatidine (Mode of action, uses and therapeutic efficacy are same) Uses Heal gastric and duodenal ulcers Relieve symptoms of gastro-esophageal reflux disease Prophylactic use may reduce bleeding from gastro-duodenal erosions in hepatic coma and conditions requiring intensive care
16 H2 Receptor antagonists Cimetidine Side effects Weak antiandrogenic gynaecomastia, sexual dysfunction Elderly - CNS disturbances P450 enzyme inhibitor
17 H2 Receptor antagonists Ranitidine, famotidine, nizatidine The drugs do not inhibit hepatic microsomal enzymes Do not block androgen receptors Metabolism and excretion Metabolized Excreted unchanged by the kidney Ranitidine 50% 50% Famotidine 25% 75% Nizatidine 10% 90%
18 H2 Receptor antagonists Cautions Renal impairment Pregnancy Breast feeding Can mask the symptoms of gastric carcinoma Side effects Diarrhoea and other GI disturbances Bradycardia Blood disorders Skin reaction
19 Mechanism PROTON PUMP INHIBITORS Inhibit the proton pump of the gastric parietal cells Omeprazole,esomeprazole,lansoprazole,pantoprazole and rabeprazole Similar in efficacy and mode of action
20 PROTON PUMP INHIBITORS Uses Treatment of gastric and duodenal ulcers In combination with anti-bacterials for the eradication of Helicobactor pylori Following endoscopic treatment of severe peptic ulcer bleeding, proton pump inhibitor reduces the risk of rebleeding and the need for surgery
21 Uses PROTON PUMP INHIBITORS Treatment of dyspepsia and gastro-oesophagealreflux disease Prvention and treatment of NSAID- associated ulcers Dosage forms available: Capsules, orodispersible tablets, Intravenous injectios/infusions
22 Omeprazole PROTON PUMP INHIBITORS Pro-drug Irreversibly inactivate the proton pump H+/K+-ATPase regenerates when proton pump inhibotors are discontinued Is degraded at low ph and must be given in enteric coated granules Systemic availability increases with does and also with time, owing to decreased inactivity of the pro-drug as gastric acidity is redused
23 Omeprazole PROTON PUMP INHIBITORS Adverse effects GI disturbances Omeprazole inhibits the cytochrome P450 system Decreasing the metabolism of Warfarin,diazepam,carbamazepine,phenytoin Long term use may increase the risk of gastric neoplasia
24 DRUGS TO ENHANCE MUCOSAL RESISTANCE Bismuth chelate Mechanism of action Chelate with protein in the ulcer base to forma coating that protects the ulcer from the adverse influences of acid, pepsin and bile Suppress growth of Helicobactor pylori, especially when combined with an antimicrobial
25 DRUGS TO ENHANCE MUCOSAL RESISTANCE Bismuth chelate Uses Treatment of benign gastric and duodenal ulcers Side effects Darkens tongue, teeth and stool Renal excretion avoid in RF
26 DRUGS TO ENHANCE MUCOSAL RESISTANCE Sucralfate Complex salt of sucrose sulphate and aluminium hydroxide Mechanism of action: At acidic ph the aluminium moiety is released. Develops a strong negative charge and binds to positively charged protein molecules that transude from damaged mucosa Results in a viscous paste that adheres selectively and protectively to the ulcer base Also binds to and inactivates pepsin
27 DRUGS TO ENHANCE MUCOSAL RESISTANCE Sucralfate Adverse effects Constipation, otherwise well tolerated Effective only in acid conditions An antacid should not be taken 30min before or after a does of sucralfate Interferes with absorption of co-administered ciprofloxacin, theophylline, digoxin, phenytoin and amitriptyline
28 DRUGS TO ENHANCE MUCOSAL RESISTANCE Misoprostol Synthetic analogue of prostaglandin E1 Protects against the formation of gastric and duodenal ulcers in patients on NSAIDs Cytoprotective mechanisms chronic gastric and duodenal ulcers unrelated to NSAID Due to an anti secretary properties Adverse effects Diarrhoea and abdominal pain Vaginal spotting and dysmenorrhoea Abuse of misoprostol read Contraindication Pregnancy or for women planning to become pregnant
29 Helicobactor pylori ERADICATON Sensitive to metronidazole, amoxicilin, clarithromycin, tetracycline and bismuth salts Efficacy of antimicrobials can be increased considerably by coadministration of a proton pump inhibitor Indications Gastric and duodenal ulcers not associated with NSAID use Not indicated for reflux oesophagities
30 Helicobactor pylori ERADICATON 3 drug regime Acid suppression : proton pump inhibitor Effective combination of antimicrobials : Clarithromycin + Amoxicillin Clarithromycin + Metronidazole
31 Helicobactor pylori ERADICATON Regimens recommended Proton pump inhibitor in full dose + Clarithromycin 500 mg + Amoxicillin 1 g b.d. 7 days
32 Helicobactor pylori ERADICATON Regimens recommended Proton pump inhibitor in full dose + Clarithromycin 250 mg + Metronidazole 400 mg b.d. 7 days
33 Gastro-esophageal Reflux Disease (GERD) GERD is defined as A condition which develops when reflux of stomach contents cause troublesome symptoms and /or complications Spontaneous transient lower esophageal sphincter relaxation -Normal physiological reflux can occur -Reflux is neutralized and cleared by advancing peristalsis which propels bicarbonate rich saliva
34 Gastro-esophageal Reflux Disease Antireflux mechanisms (GERD) Preassure of the lower esophageal sphincter Flap value mechanism of the intra-abdominal esophagus Mucosal rosette formed by folds of the gastric mucosa Contraction of the crural diaphragm at the LOS
35 GASTRO-OESOPHAGEAL REFLUX DISEASE (GORD) Factors contributing to pathological reflux Incompetence of the gastro-oesophageal sphincter Delayed oesophageal clearance of acid Delayed gastric emptying The commonest symptom is heartburn
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38 Drugs GASTRO-OESOPHAGEAL REFLUX DISEASE (GORD) Antacids Helpful in controlling mild reflux symptoms when taken regularly after meals with additional doses as needed. Preparations combined with alginates Alginate produces a viscous floating gel that blocks reflux and protectively coats the oesophagus
39 GASTRO-OESOPHAGEAL REFLUX DISEASE (GORD) H2- receptor antagonists Useful in the short-term management of mild oesophagities Proton pump inhibitors Currently the most effective drugs Pro-kinetic drugs Metoclopramide domperidone
40 Metoclopramide Action Centrally blocking dopamine D2 receptors in the CTZ Peripherally enhancing the action of acetyicholine at muscarinic nerve endings in the gut Effects Raises the tone of the lower oesophageal sphincter Relaxes the pyloric antrum and duodenal cap Increases peristalsis and emptying of the upper gut Metabolized in the liver (t ½ 4h)
41 Metoclopramide Uses Nausea and vomiting associated with gastrointestinal disorders, and with cytotoxic drugs and radiotherapy An effective antiemetic in migraine A pro-kinetic agent Adverse reactions Extra pyramidal dystonia(torticollis, facial spasms, trismus, oculogyic crises). Long-term use may cause tardive dyskinesia in the elderly Stimulates prolactin release and may cause gynaecomastia and location
42 Domperidone Selective dopamine D2-receptor antagonist No acetylcholine-like effect Does not readily penetrate the blood-brain barrier Less risk of adverse effect in the CNS. Uses Nausea or vomiting associated with gastrointestinal disorders and with cytotoxic and other drug treatments It may cause gynaecomastia and galactorrhoea
43 Thank you
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