Drugs used in the treatment of peptic ulcer

Gastric Defenses Against Acid 1- Esophageal defense: the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus. 2- Stomach defense: (require adequate mucosal blood flow because of the high metabolic activity and oxygen requirements of the gastric mucosa) a) Secretion of a mucus layer that protects gastric epithelial cells. Mucus production is stimulated by prostaglandins E2 and I2, which also directly inhibit gastric acid secretion by parietal cells. Drugs that inhibit prostaglandin formation (are alcohol and NSAIDs) decrease mucus secretion and predispose to the development of acid-peptic disease. b) Secretion of bicarbonate ions by superficial gastric epithelial cells. Bicarbonate neutralizes HCl.

Types of gastric HCl secretion 1- Nocturnal (basal) acid secretion: depend on histamine 2- Meal stimulated acid secretion: stimulated by: Gastrin Acetylcholine Histamine

Phases of gastric secretion 1) Cephalic Phase 2) Gastric Phase 3) Intestinal Phase

Phases of gastric secretion Stimuli Pathway Cephalic (stimulate) Sight, smell, taste or thought of food Vagus (M3 receptors) Histamine (H2 receptor) Gastrin Gastric (stimulate) Food in the stomach Stretch: local reflex (M3 receptors) Chemical substances in food (gastrin) Increase pH: Inhibition of somatostatin release Intestinal (inhibit) Chyme in the duodenum

Regulatory molecules that stimulate acid secretion Acetylcholine Produced from nerve endings and stimulate M3 receptor on: Parietal cells (produce HCl) Enterochromaffin cells and Mast cells (produce histamine) G cells (produce gastrin) Histamine Produced by enterochromaffin cells and Mast cells in response to stimulation of M3 receptors (by acetylcholine) and CCK3 receptors by gastrin. It stimulates parietal cells to produce HCL Gastrin Produced by G cells in response to stimulation of M3 receptors by acetylcholine and stretch and by chemical substances in food

Mechanism of HCl secretion

Steps of gastric acid secretion by parietal cells * Chloride (Cl¯) and hydrogen ions are secreted actively from the cytoplasm of parietal cells into the lumen of the canaliculus where and they combine into HCl then secreted into the lumen of the stomach * Hydrogen ions are produced in the parietal cells by the action of the enzyme carbonic anhydrase which catalyses the reaction between carbon dioxide and water, in which carbonic acid is produced. This acid immediately dissociates into hydrogen ions and carbonate ions. Hydrogen ions leave the cell by the aid of H+/K+ ATPase pump. * Chloride ions are transported across the basolateral membrane of the parietal cells into the parietal cells in exchange with bicarbonates

Ca++ Ca++ Protein Kinase ACh PGE1 Gastrin Histamine PGE receptor _ H2 M3 Adenyl cyclase + Gastrin receptor + + Ca++ ATP cAMP Ca++ + + + Protein Kinase (Activated) K+ + H+ Parietal cell Proton pump Lumen of stomach Gastric acid

Ca++ Ca++ Protein Kinase ACh PGE1 Gastrin Histamine _ H2 M3 Adenyl cyclase + Gastrin receptor PGE receptor + + Ca++ ATP cAMP Ca++ + + + Protein Kinase (Activated) K+ H+ + K Parietal cell Proton pump Lumen of stomach Gastric acid

I- Agents that reduce gastric acidity Proton pump inhibitors H2 receptor antagonists Muscarine receptor antagonists Antacids II- Mucosal protective agents Sucralfate Prostaglandin (PGE1) agonists (misoprostol) Colloidal bismuth compounds Carbenoxolone

I- Agents that reduce gastric acidity Proton pump inhibitors H2 receptor antagonists Muscarine receptor antagonists Antacids

I- Agents that reduce increased gastric acidity 1- Proton pump inhibitors Proton pump inhibitors are the most potent suppressors of gastric acid secretion Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole Action: Inhibit both fasting (basal) and meal-stimulated HCl secretion by irreversible inactivation of the proton pump in the wall of parietal cells

Proton pump inhibitors Pharmacokinetics: Proton pump inhibitors are prodrugs that require activation in an acid environment 1- Oral forms are prepared as acid resistant formulations that release the drug in the intestine (because they are degraded in acid media) 2- After absorption, they are distributed by blood to parietal cells 3-They irreversibly inactivate the proton pump molecule (providing 24- to 48-hour suppression of acid secretion, despite the much shorter plasma half-lives of the parent compounds).

Proton pump inhibitors Pharmacokinetics 4- they should be given on an empty stomach because food affects absorption 5- 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 drugs that inhibit acid secretion, such as H2-receptor antagonists, might be predicted to lessen the effectiveness of the proton pump inhibitors )

Proton pump inhibitors Pharmacokinetics 6- Maximal effect is reached after 3 to 4 days of administration (the time required to fully inactivate the proton pumps) 7- Their effects persists for 3 to 4 days after stopping the drug (the time required for full recovery of the proton pumps) 8- Metabolized by the liver (dose reduction is necessary in severe liver impairment) 9- Minimal excretion by the kidney ( no dose reduction is necessary in renal impairment)

Proton pump inhibitors Adverse effects Few 1- The most common are GIT troubles in the form of nausea, abdominal pain, constipation, flatulence, and diarrhea 2- Subacute myopathy, arthralgias, headaches, and skin rashes 3- Prolonged use leads to vitamin B12 deficiency (because HCl is important for releasing vitamin B12 from food). 4-Hypergastrinemia which may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )

Proton pump inhibitors Drug interactions Metabolized by cytochrome P450 enzymes and may interfere with the metabolism of drugs metabolized with cytochrome P45o such as warfarin, diazepam and cyclosporine increasing their levels and producing toxicity

Proton pump inhibitors Therapeutic uses Gastroesophageal reflux disease (GERD) Gastric and duodenal ulcers 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.

H2 receptor antagonists - Ranitidine Famotidine Nizatidine Elimination Small amounts are metabolized by the liver (liver disease is not an indication for adjusting dose) Drug and metabolites are excreted by the kidney (dose should be reduced in kidney disease) Mechanism of action Suppression of HCl by competitive inhibition of H2 receptors in parietal cells. less potent than proton pump inhibitors They suppress basal gastric acid secretion more than meal stimulated secretion Uses 1- Gastroeophageal reflux disease (uncomplicated) 2- Gastric and duodenal ulcers 3- Prevention of occurrence of stress ulcers Adverse effects Few 1- GIT: diarrhea and constipation. 2- Headache, dizziness and fatigue and muscle pain 3- Hypergastrinemia Drug interactions Agents that decrease gastric acidity alter the rate of absorption and subsequent bioavailability of H2-receptor antagonists

Muscarine receptor antagonists Pirenzepine Telenzepine Mechanism of action: reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia ( receptors on parietal cells are M3). Adverse effects: They produce anticholinergic side effects at doses that block HCl secretion Because of poor efficacy, side effects and delay of gastric emptying, they are not used in treating acid peptic disease

I- Agents that reduce increased gastric acidity 4- Antacids Mechanism of action: 1- Reduction of intragastric acidity by reacting with gastric HCl to form salt and water 2- Stimulate mucosal PG production Types: NaHCO3 1- Sodium bicarbonate CaCO3 2- Calcium carbonate 3- Al hydroxide Al(OH)3 Mg(OH)2 4- Magnesium hydroxide frt

Chemical reactions of antacids with HCl in the stomach

Effects of antacids 1- Neutralize excess HCl in the stomach (by the reacted part) 2- Effect of the unreacted part 3- Effects of the products of the reaction Raising gastric pH from 1.3 to 1.6 neutralizes 50% of gastric acid. Raising gastric pH point from 1.3 to 2.3 neutralizes 90% of the gastric acid.

Effects of antacids 1- Sodium bicarbonate 1- Effect of the reacted part: rapid neutralization of the gastric HCL 2- Unreacted sodium bicarbonate could be absorbed causing metabolic alkalosis if given in high doses or in patients with impaired renal function. 3- NaCl produced by the reaction could be absorbed causing fluid retention and aggrevating hypertension 4- CO2 produced causes gastric distention and increased production of gastrin which causes rebound acidity 5- High doses given with dairy products can lead to hypercalcemia and renal insufficiency (milk-alkali syndrome)

Effects of antacids 2- Calcium carbonate 1- Effect of the reacted part: less rapid neutralization of the gastric HCL 2- CO2 produced causes gastric distention and increased production of gastrin which causes rebound acidity 3- High doses given with dairy products can lead to hypercalcemia and renal insufficiency (milk-alkali syndrome)

Effects of antacids 3- Aluminum hydroxide 1- Effect of the reacted part: slow neutralization of the gastric HCL 2- No metabolic alkalosis 3- Unabsorbed aluminum salts may cause constipation

Effects of antacids 4- Magnesium hydroxide 1- Effect of the reacted part: slow neutralization of the gastric HCL 2- No metabolic alkalosis 3- Unabsorbed magnesium salts may cause osmotic diarrhea 4- Magnesium could be absorbed and excreted by the kidney and therefore should not be given to patients with renal insufficiency for a long tine

Sodium bicarbonate Calcium carbonate Mg hydroxide Aluminum hydroxide Reaction with HCl Reacts rapidly Reacts slowly Products of the reaction NaCl and CO2 which produces gastric distension and aggrevate hypertension CaCl2 and CO2 which produces gastric distension MgCl2 and H2O AlCl2 and H2O Effect of unreacted antacids absorbed causing alkalosis if given in high doses or in patients with renal insufficiency Unabsorbed causing osmotic diarrhoea Unabsorbed causing constipation Precautions Affect absorption of other drugs therefore should not be given within 2 hours of tetracycline or iron

Mucosal protective agents 1- Sucralfate Sucralfate = complex aluminum hydroxide + sulfate + sucrose Mechanism of action: 1- in acidic environment of the stomach, it forms a viscous paste that binds to ulcers or erosions for 6 hours forming a physical barrier against hydrolysis of mucosal proteins by pepsin. 2- stimulates mucosal prostaglandins and bicarbonate production 3- Sucralfate binds bile salts (used to treat individuals with biliary gastritis

Mucosal protective agents 1- Sucralfate Therapeutic uses: Prophylaxis of stress ulcers in critically ill patients (increased pH of the stomach increases the possibility of nosocomial infections. Conditions associated with mucosal ulceration not due to acid production as aphthous ulcers and by rectal enema solitary rectal ulcers.

Mucosal protective agents 1- Sucralfate Administration: Since it is activated by acid, sucralfate should be taken on an empty stomach 1 hour before meals. The use of antacids within 30 minutes of a dose of sucralfate should be avoided.

Mucosal protective agents 1- Sucralfate Adverse Effects: Constipation Precautions: should be avoided in patients with renal failure (because some aluminium is absorbed). Should be taken at least 2 hours after the administration of other drugs as phenytoin and digoxin (forms a viscous layer in the stomach that may inhibit absorption of drugs)

Mechanism of gastric protection Mucosal protective agents 2- Prostaglandin Analogs: (Misoprostol = Synthetic analog of prostaglandin E1) Prostaglandins produced by the gastric mucosa Prostaglandin Mechanism of gastric protection PGE1 Inhibit histamine-stimulated gastric acid secretion Stimulation of mucin and bicarbonate secretion Increase mucosal blood flow PGI2 (prostacyclin)

Mucosal protective agents 2-Misoprostol Actions: Inhibit histamine-stimulated gastric acid secretion Stimulation of mucin and bicarbonate secretion Increase mucosal blood flow Therapeutic uses: Prevent ion of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)

Mucosal protective agents 2-Misoprostol Adverse Effects: Diarrhea, with or without abdominal pain and Exacerbations of inflammatory bowel disease and should be avoided in patients with this disorder. Contraindications: Inflammatory bowel disease Pregnancy (may cause abortion)

Mucosal protective agents 3- Colloidal bismuth compounds (Bismuth subsalicylate) Pharmacological actions: 1- Undergoes rapid dissolution in the stomach into bismuth and salicylates. 2- Salicylates are absorbed 3- Bismuth coats ulcers and erosions protecting them from acid and pepsin and increases prostaglandin and bicarbonate production Uses: -Treatment of dyspepsia and acute diarrhoea

Specific acid dyspeptic disorders and therapeutic strategies Gastro-esophageal reflux disease 1- Mild: H2 receptor antagonists (twice daily) 2- Sevre: Proton pump inhibitors once daily (for 8 weeks) 3- Antacids are recommended only for the patient with mild, infrequent episodes of heartburn. 4- Severe with nocturnal acid breakthrough: proton pump inhibitors twice daily. If symptome persist, H2 receptor antagonist is added at night Helicobacter pylori infection (H. pylori) Triple therapy for 14 days: [Proton pump inhibitor + clarithromycin 500 mg + (metronidazole 500 mg or amoxicillin 1 g)] twice a day. NSAID-related Ulcers 1- Proton pump inhibitors (best) 2- H2 receptor antagonist 3- Misoprostil Peptic ulcer Proton pump inhibitors