H2 Blockers and Proton Pump Inhibitors Dr. : Asmaa Fady MD., MSC, M.B, B.Ch اسم ورقم المقرر – Course Name and No. 4/27/2019

Learning objectives: By the end of the lecture, the student should, Understand the key points of pathophysiology of the peptic ulcer disease Enumerate various classes of drugs used in peptic ulcer disease Define the characteristic pharmacokinetics, pharmacodynamics and side effects of H2 receptor blockers and PPI drugs used in peptic ulcer disease. Know the cytoprotective drugs mainly misoprostol and its use in NSAIDs-induced peptic ulcer. اسم ورقم المقرر – Course Name and No. 4/27/2019

Pathogenesis of peptic ulcer: Peptic ulcer is a break in the gastric or duodenal mucosa that arises when the normal mucosal defensive factors are impaired or overwhelmed by aggressive luminal factors. This imbalance results in any degree of gastrointestinal mucosal irritation, inflammation or ulceration. اسم ورقم المقرر – Course Name and No. 4/27/2019

Pathogenesis of peptic ulcer: Aggressive factors Defense factors a- HCl. a- Prostaglandins (E & I) b- Pepsin. b- Mucus. c- Helicobacter Pylori. c- Bicarbonates d- Bile salts. d- Blood supply e- Mucosal regeneration اسم ورقم المقرر – Course Name and No. 4/27/2019

Clinical Features of peptic ulcers 1. Symptoms & signs: Epigastric pain & tenderness. Anorexia, Nausea & Vomiting. Hemorrhage 2. Investigations Endoscopy Presence of H. pylori: Endoscopic biopsy, serological test & Urea breath test. Associated Complications: 1- Upper gastrointestinal bleeding (patients may present with hematemesis, melena, fatigue caused by anemia, or syncope). 2- Perforation. 3- Obstruction. Patients with recurrent duodenal or pyloric channel ulcers may develop pyloric stenosis 4-Silent ulcers and complications are more common in older patients and in patients taking NSAIDs. 4/27/2019

Goals of Therapy: 1- Relief of pain. 2- Promotion of healing. 3- Prevention of recurrence. 4- Preventing ulcer complications اسم ورقم المقرر – Course Name and No. 4/27/2019

Drug therapy used in Ttt of peptic ulcer A) Antacids (Neutralization of secreted HCl) B) Anti-secretory Drugs (Reduction or inhibition of Acid Secretion) C) Mucosal Protectives (Enhancement of Mucosal Resistance) D) Eradication of H. pylori. E) Other adjuvant Drugs.

اسم ورقم المقرر – Course Name and No. 4/27/2019

Drug therapy used in Ttt of peptic ulcer 1) Antacids (Neutralization of secreted HCl): - Aluminum Hydroxide + Magnesium hydroxide 2) Antisecretory Drugs (Reduction of Acid Secretion): I- H2-Receptor Blockers. II- Proton Pump Inhibitor (H+/K+ ATPase Inhibitors). III- Antimuscarinic Drugs (M3 receptors) IV- Gastrin Antagonists. V- Prostaglandins (E &I) 3) Mucosal Protectives (Enhancement of Mucosal Resistance): 1- Sucralfate. 2- Prostaglandins 4) Eradication of H. pylori: 1- Metronidazole. 2- Bismuth compounds. 3- Amoxicillin. 4- Tetracycline. 5- Clarithromycin. 5) Other adjuvant Drugs: 1- Sedatives or Tranquillizers e.g. Diazepam (# Psychic effect on acid secretion) 2- Tricyclic Antidepressants.

1. Antacids: very weak agents They Produce: 1- Chemical Neutralization of HCl Relief of Pain. 2- Elevation of pH Activity of Pepsin. 3- Some PGs & Eradication of H. pylori. Useful in treatment of: 1- Peptic Ulcer Rapid relief Supplement other drugs during initiation of treatment. 2- Gastro-Esophageal Reflux Disease (GERD) & Heart burn. 3- Gastritis Classification: 1- Chemical Anti-Acids. 2- Physical Anti-Acids. Multiple side effects. 4/27/2019

2. Anti-secretory Drugs (Reduction of Acid Secretion): H2-Receptor Blockers: Cimetidine- ranitidine- famotidine- Nizatidine Anti-muscarinic Drugs (M3): Pirenzepine. Gastrin Antagonists: Gastrin receptor blockers: Proglumide. N.B.: Gastrin is a hormone secreted by cells in the pyloric glands and increases HCL and pepsin secretion Prostaglandins: Misoprostol. Proton Pump Inhibitor (irreversible H+/K+ ATPase Inhibitors): Omeprazole- pantoprazole- lansoprazole- rapeprazole- esomeprazole. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: I) H2 receptor blockers: * Cimetidine Pharmacokinetics: Well Absorbed Orally & Parentally. Distributed ALL over the body. (Passes BB & Placental barrier). 1/3 Metabolized in liver. It is a hepatic microsomal enzyme inhibitor. 2/3 Excreted Unchanged in Urine & Milk. Pharmacodynamics: 1- Selective Competitive Blocker of Histamine H2-receptors. No action on H1 or H3. ( 70%) of HCl secretion. 2- Reduces gastric acidity: a- Both volume & Hydrogen ion concentration. b- Formation of pepsin. 3- Does Not affect gut motility. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: I) H2 receptor blockers:* Cimetidine Therapeutic Uses of Cimetidine: 1- Peptic Ulcer (Gastric & Duodenal): *Promotes the healing of the ulcers & prevent their recurrence. **Decrease the dose in Renal & hepatic patients. 2- Ulcers due to Stress and Iatrogenic ulcers. 3- I.M. or I.V. in Upper G.I.T. bleeding after burn, trauma or acute renal failure 4- Pre-anesthetic in emergency operation & labor to prevent aspiration of gastric HCl. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: I) H2 receptor blockers:* Cimetidine Side Effects & Drug Interactions of Cimetidine: 1- Sudden stop : Recurrence of the ulcer & Bleeding. 2- GIT Upsets : Constipation or diarrhea. 3- Hypersensitivity reactions e.g. Skin rash & Itching. 4- Affect liver & kidney (increases Serum creatinine). 5- Hepatic Microsomal Enzyme Inhibitor ( decreases Cytochrome P450): decrease Metabolism of Warfarin, Theophylline & Phenytoin. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: I) H2 receptor blockers:* Cimetidine Side Effects & Drug Interactions of Cimetidine: 7- In Males (Anti-Androgen) : Gynecomastia & Spermatic count. 8- In Females (Increases Prolactin) : Galactorrhea & Infertility. 9- Confusion and delirium in old age (pass BBB) 10- Blood Dyscrasias : Agranulocytosis, Aplastic Anemia & Thrombocytopenia. 11- Muscle pain. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: I) H2 receptor blockers: 2. Anti-secretory drugs: I) H2 receptor blockers: * Ranitidine, Nizatidine and Famotidine 1-Pharmacokinetics similar to Cimetidine BUT LONGER & Not pass BBB. 2- Pharmacodynamics Similar to Cimetidine BUT STRONGER (5-10 Times). 3- Side Effects similar to Cimetidine BUT SAFER : a- NO Hepatic Microsomal Enzyme Inhibition. b- NO effect on males or females. d- NO BBB (NO CNS effects in Elderly). Famotidine (Pepcid): the strongest one. Extremely safe drugs اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: II) Proton Pump Inhibitors (PPIs) 1- Omeprazole (Losec) 2- Esomeprazole (Nexium) 3- Lansoprazole (Lanzor) 4- Pantoprazole (Controloc) 5- Rabeprazole Weak basic drugs. Acid sensitive drugs (destructed by HCL): use enteric coated tablets. Prodrugs. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: II) Proton Pump Inhibitors (PPIs) Pharmacokinetics Well absorbed orally. Affected by gastric acidity. Given as enteric coated preparation. Should be given on empty stomach. Pantoprazole also given intravenously. Pass BBB & pass Placental barrier . Concentrated in acid canaliculi of gastric parietal cells (weak bases) Hepatic metabolism. Metabolites are excreted in urine. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: II) Proton Pump Inhibitors (PPIs) Pharmacodynamics 1- Prodrugs: Activated in the acid environment of the secretory canaliculi of the parietal cells of the stomach. Since it requires acid for activation. 2- Irreversible inhibitor of H+/K+ ATPase enzyme. Their effect is prolonged until synthesis of new H+/K+ ATPase enzyme. 3- decrease gastric acidity up to 100%. BUT NO effect on gastric motility. 5- increase Gastrin secretion (unimportant) اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: II) Proton Pump Inhibitors (PPIs) Therapeutic uses: 1- peptic ulcer. 2- GERD (gastro-esophageal reflux disease). Extremely safe drugs اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: II) Proton Pump Inhibitors (PPIs) Side effects and drug interactions: 1- CNS : Headache, Dizziness & Drowsiness. 2- GIT : Nausea, Diarrhea & Abdominal colic. 3- Omeprazole (HME I) decreases Metabolism of Warfarin, Theophylline & Phenytoin. 4- Prolonged use (years): decrease Ca absorption : ppt. osteoporosis and bone fractures. Decreased Vit. B12 Vit. B 12 deficiency anemia. Increase the risk of (bacterial colonization): respiratory & enteric infections due to the loss of the antibacterial properties of an acidic environment. اسم ورقم المقرر – Course Name and No. 4/27/2019

2. Anti-secretory drugs: III- Anti-Muscarinic Drugs Pirenzepine & Telenzepine (atropine substitutes) Selective M1-blockers Acidity. Selective blockade of M1 receptors on vagal ganglia innervating the stomach motility More effective when used with other drugs e.g. H2- blockers. Adverse effects (atropine like reactions). Contraindications: glaucoma & prostatic hypertrophy. اسم ورقم المقرر – Course Name and No. 4/27/2019

3. Mucosal Protective Agents They act by Enhancement of Mucosal Resistance via increasing protective PG level. PG E2 & I2 (Misoprostol) Sucralfate. Colloidal Bismuth compounds. اسم ورقم المقرر – Course Name and No. 4/27/2019

3. Mucosal Protective Agents: a. Misoprostol: PG E1 analogue. Mechanism: 1- decrease H Cl secretion (Anti-Secretory). 2- increase Mucus secretion 3- increase Blood supply to the mucosa. 4- increase HCO3 secretion. 5- Promotes healing of ulcer (vasodilators, promote healing) 6- Prevent gastric ulcer induced by corticosteroids or NSAID (iatrogenic ulcer) Side Effects: a- Oxytocic: ppt. uterine contractions: (Abortion). Contraindicated in pregnancy. b- Diarrhea, Nausea & abdominal pain اسم ورقم المقرر – Course Name and No. 4/27/2019

3. Mucosal Protective Agents: b. Sucralfate : sucrose - AL++ - sulfate Mechanism: in the presence of HCl, it dissociates into sulfate sucrose and AL hydroxide: Sulfate sucrose part Attach to proteins present in mucous and convert it into gel which cannot be destructed by pepsin. The negative charge of sulfate allows demulcent action on ulcer base. Adsorb destructive bile and pepsin. ↑ PGs secretion Side Effects: due to AL 1- Constipation 2- ↓ Absorption of food & drugs (cimetidine – digoxin – phosphate – tetracycline – quinolone – ketoconazole- iron) اسم ورقم المقرر – Course Name and No. 4/27/2019

3. Mucosal Protective Agents: c. Colloidal Bismuth compounds Increase PGs, Coats ulcer, stimulates mucus & bicarbonate secretion Direct antimicrobial activity against H. pylori. Weak Antacid action. May cause blackening of stools & tongue Not used for long periods – bismuth toxicity. اسم ورقم المقرر – Course Name and No. 4/27/2019

4. Eradication of Helicobacter pylori Triple Therapy Quadruple therapy اسم ورقم المقرر – Course Name and No. 4/27/2019

Triple Therapy The BEST among all the Triple therapy regimen is: Omeprazole /or Lansoprazole - 20 / 30 mg bd Clarithromycin - 500 mg bd Amoxycillin /or Metronidazole - 1gm / 500 mg bd Given for 14 days followed by P.P.I for 4 – 6 weeks Short regimens for 7 – 10 days not very effective اسم ورقم المقرر – Course Name and No. 4/27/2019

Quadruple Therapy Given when Triple Therapy fails Omeprazole or / Lansoprazole - 20 / 30 mg bd Bismuth subsalycilate - 2 tabs qid Metronidazole - 250 mg qid Tetracycline - 500 mg qid اسم ورقم المقرر – Course Name and No. 4/27/2019

اسم ورقم المقرر – Course Name and No. 4/27/2019