Pharmacology of GI Drugs 1: Gastric Acid Reducing Drugs PDF

Pharmacology of GI Drugs 1: Gastric acid reducing drugs Erin St. Onge, Pharm.D. Clinical Associate Professor Pharmacy Education and Practice Suggested Reading Sharkey KA, MacNaughton WK. Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease (Ch. 53) In: Bru...

Pharmacology of GI Drugs 1: Gastric acid reducing drugs Erin St. Onge, Pharm.D. Clinical Associate Professor Pharmacy Education and Practice Suggested Reading Sharkey KA, MacNaughton WK. Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease (Ch. 53) In: Brunton L. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, McGraw-Hill Professional, New York, NY, 14th Edition, 2024 (Available in Access Pharmacy) 2  Learning Objectives Compare and contrast the therapeutic and adverse effects of the following drug classes: – Antacids – H2 receptor antagonists (H2RAs) – Proton pump inhibitors (PPIs) – Potassium-competitive acid blockers (PCABs) – Mucosal defense enhancing drugs Describe relevant pharmacokinetic characteristics of each of these drug classes Identify the most common/serious drug interactions, precautions, and contraindications of each of these drug classes 4 Principles of Therapy Disease states – GERD – PUD – Stress ulcers – Zollinger-Ellison syndrome Basis of therapy – Neutralize excess acid – Reduce gastric acid secretion – Enhance gastric mucous defense 5  Antacids MOA: physically neutralize gastric acid Agents – Calcium carbonate – Magnesium hydroxide – Aluminum hydroxide – Sodium bicarbonate - not recommended 6 Calcium Carbonate Brand names – Tums, Rolaids Rapidly neutralizes acid Moderate neutralizing ability Ca2+ may induce rebound acid secretion Adverse effects: belching, flatulence, nausea; constipation 10% of Ca2+ is absorbed – short-term hypercalcemia Caution in renal disease or kidney stones 7  Magnesium Hydroxide- Mg(OH)2 Rapidly neutralizes acid Highly osmotic ion Antacid-Laxative when used alone – Phillips® Milk of Magnesia Antacid only - combined with Al(OH)3 – Maalox®, Mylanta® Caution in renal impairment, geriatric patients Chelates other drugs in the GI tract 8 Aluminum Hydroxide Slowly neutralizes gastric acid Amphojel® – Treatment for hyperphosphatemia May cause constipation As an antacid combined with Mg Caution in renal impairment – Aluminum toxicity, encephalopathy Chelates other drugs in the GI tract Increased bone resorption, osteoporosis with prolonged use 9 Antacids – Considerations for Use Dosing – Dose 1 hr after meals and at bedtime – Liquids better than tablets – Tablets – chew thoroughly and follow with water Drug interactions – Chelation - quinolones, tetracyclines, levothyroxine Administer antacids 2 hours before or after other medications Levothyroxine – administer at least 4 hours before or after – Increased gastric pH – decreased absorption of iron, certain HIV medications, some azole antifungals 10 Principles of Therapy Disease states – GERD – PUD – Stress ulcers – Zollinger-Ellison syndrome Basis of therapy – Neutralize excess acid – Reduce gastric acid secretion – Enhance gastric mucous defense 11 12 H2 Receptor Antagonists (H2RAs) MOA: – Reversibly compete with histamine for binding H2 receptors on the parietal cell – Inhibit acid secretion by ~70% – Block basal and nocturnal acid production as well as some stimulated secretion Available agents: cimetidine, famotidine, nizatidine* IV formulations – famotidine, cimetidine Duration of effect is 3-12 hrs Drugs and metabolites mainly renally excreted 13 Adverse Effects of H2RAs Common: – Diarrhea, constipation, drowsiness, fatigue, headache, dizziness Rare: – Thrombocytopenia – Vitamin B12 deficiency CNS: confusion, delirium, hallucinations – Elderly, IV formulation Cimetidine: gynecomastia, impotence 14  H2RA Drug Interactions Drug interactions – All H2RAs: agents affected by increased gastric pH – Cimetidine Inhibits multiple CYPs (1A2, 2C9, 2D6, 3A4) Eletriptan (due to CYP3A4) – contraindicated within 72 hrs Warfarin – increased INR Phenytoin – increased levels (toxicity); avoid use Benzodiazepines– increased levels thus increased adverse effects Many others 15 16  Proton Pump Inhibitors (PPIs) MOA: inhibit gastric H+/K+-ATPase (aka proton pump) – Inhibit acid secretion regardless of stimuli – Reduce acid secretion by 80-95% Prodrugs: require activation in acid environment – Rapidly absorbed into systemic circulation – Diffuse into parietal cells and are activated – Bind covalently with sulfhydryl groups in H+/K+-ATPase – Irreversibly inhibit proton pump 17 Proton Pump Inhibitors Available agents – Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Most formulated as enteric-coated or delayed- release to prevent degradation in stomach acid IV formulations – esomeprazole, pantoprazole Dosing - most 30-60 minutes before meal Full effects may take several days 18 PPIs - Considerations for Use Adverse effects: diarrhea, headache, nausea, constipation, flatulence, abdominal pain Drug Interactions – All PPIs can affect drugs with pH-dependent absorption ketoconazole, iron salts, protease inhibitor (atazanavir) – Omeprazole: inhibits 2C19 and 2C9; increased levels of warfarin, diazepam, phenytoin – Clopidogrel: converted to active metabolite via CYP 2C19 ‒ Omeprazole, esomeprazole inhibit CYP 2C19 19 20 Potassium-Competitive Acid Blockers (PCABs) MOA: inhibits the gastric H+/K+-ATPase (aka proton pump) in a K+ dependent manner – Suppresses basal and stimulated acid secretion – Does not require activation by acid – Binding to proton pump is reversible Agent: vonoprazan Dosage forms: oral tablet – Can be taken without regard to food 21  PCABs Adverse effects: nasopharyngitis, diarrhea, constipation, flatulence, dyspepsia, headache, abdominal pain Drug interactions – CYP3A4 inducers, drugs with pH dependent absorption Compared to PPIs – Rapid onset of action – Prolonged duration of action – Accumulate at higher concentrations in parietal cell 22 Principles of Therapy Disease states – GERD – PUD – Stress ulcers – Zollinger-Ellison syndrome Basis of therapy – Neutralize excess acid – Reduce gastric acid secretion – Enhance gastric mucous defense 23 24 Misoprostol (Cytotec®) Prostaglandin E1 analog – Enhances mucus and bicarbonate production – Reduces acid secretion Indication – prevention of NSAID-induced ulcers Considerations – Multiple daily dosing – Adverse effects – diarrhea, abdominal cramps (limits use); can exacerbate inflammatory bowel disease – Contraindicated in pregnancy 25 Sucralfate (Carafate®) Sucrose sulfate complex with Al(OH)3 Activated by acid to form viscous paste Binds and coats ulcer areas for up to 6 hours May stimulate local prostaglandins Does NOT reduce acid appreciably Take on empty stomach Adverse effect – constipation Avoid in severe renal impairment Inhibits absorption of other drugs – phenytoin, digoxin, fluoroquinolones, ketoconazole 26 Bismuth subsalicylate Mechanism of action – Direct mucosal protective effect – Antimicrobial action against H. pylori Adverse effects – Black stool and discoloration of oral cavity/tongue – Constipation Considerations – Salicylate allergy – Avoid in children < 12 years of age due to risk of Reye’s syndrome – Increased risk of bleeding 27 Summary Basis of therapy – Neutralize excess acid Antacids – Reduce gastric acid secretion H2RAs, PPIs, PCABs – Enhance gastric mucous defense Misoprostol, Sucralfate, Bismuth 28