Phase 1 Block 1 Pharmacology Drugs to Treat Acid Secretion PDF

Phase 1 Block 1 Pharmacology Drugs to Treat Disorders of Acid Secretion Dr Dan Mitchell Warwick Medical School, Email: [email protected]  Learning Outcomes List the classes of drugs commonly used to treat disorders of acid secretion....

Phase 1 Block 1 Pharmacology Drugs to Treat Disorders of Acid Secretion Dr Dan Mitchell Warwick Medical School, Email: [email protected]  Learning Outcomes List the classes of drugs commonly used to treat disorders of acid secretion. Describe the molecular and cellular mechanisms of action of drug therapies for disorders of gastric acid secretion. Relate molecular and cellular mechanisms of drug action to responses at the tissue and organ level in the treatment of common and important disorders of gastric acid secretion.  Drugs used to Treat Disorders of Acid Secretion From the Block 1 Drugs List Also relevant to this lecture  Antacids An antacid is any substance, generally a base (alkali), which counteracts stomach acidity. They act by buffering gastric acid, thereby raising the gastric pH to levels that are less harmful to stomach tissues. Key examples: Aluminum hydroxide and magnesium hydroxide Calcium carbonate and magnesium carbonate (Familiar to many as the brand of antacid tablets, Rennie®)  Alginates Anionic polysaccharides that form a viscous gel upon binding water. Often combined with antacids for use in reflux oesophagitis. Increase the viscosity of stomach contents and can protect the oesophageal mucosa from acid reflux. The viscous gel (‘raft’) floats on the surface of the stomach contents, thereby reducing symptoms of reflux. Key example Sodium alginate (combined with sodium bicarbonate & calcium carbonate in the familiar brand Gaviscon®)  SSR - Somatostatin Cholinergic ECL nerve Muscarinic cell Gastrin Blood vessel Receptor Receptor + + ACh Histamine Gastrin + + + Muscarinic H2-Receptor Gastrin - Receptor Receptor + SSR - Somatostatin PGE2 PGE2-R - Parietal cell H+ Physiology of AA P proton pump Acid Secretion H+  Histamine H2-Receptor Antagonists Competitively inhibit histamine actions at H2-receptors. Key example: Famotidine Decrease basal and stimulated acid secretion.  SSR - Somatostatin Cholinergic ECL nerve Muscarinic cell Gastrin Blood vessel Receptor Receptor + + ACh Histamine Gastrin FAMOTIDINE + - + + Muscarinic H2-Receptor Gastrin - Receptor Receptor + SSR - Somatostatin PGE2 PGE2-R - Parietal cell H+ Physiology of AA P proton pump Acid Secretion H+  Proton Pump Inhibitors Irreversibly inhibit the H+/K+-ATPase pump, the terminal step in the acid secretory pathway. Key examples: Omeprazole, Lansoprazole Decrease both basal and stimulated acid secretion. Are more effective than H2-receptor antagonists. Are inactive at neutral pH. Accumulate in secretory canaliculi of parietal cells and are activated in acid environment. Therefore very specific.  SSR - Somatostatin Cholinergic ECL nerve Muscarinic cell Gastrin Blood vessel Receptor Receptor + + ACh Histamine Gastrin H2-antagonists + - + + Muscarinic H2-Receptor Gastrin - Receptor Receptor + SSR - Somatostatin PGE2 PGE2-R - Parietal cell H+ Physiology of AA P - proton pump Acid Secretion OMEPRAZOLE H+  Proton Pump Inhibitors From the circulation, the pro-drug (lipophilic) traverses the parietal cell and enters the canaliculus. In the acidic canaliculus, the drug is activated and “trapped” here. Drug binds to H+/K+-ATPase pump, irreversibly inactivating it. For acid secretion to resume, new H+/K+-ATPase pump molecules have to be synthesized. A single daily dose affects acid Fox, Human Physiology (McGraw-Hill) secretion for 2-3 days. Common conditions requiring drug treatment of excess acid secretion Reflux oesophagitis Peptic ulcer 1. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDS) 2. H. Pylori infection  Reflux Oesophagitis Arises from gastro-oesophageal reflux disease (GORD): the liquid content of the stomach regurgitates into the oesophagus. Reflux oesophagitis: inflammation of the lower oesophagus produced by persistent episodes of reflux.  Reflux Oesophagitis Symptoms and Complications Symptoms Heartburn Regurgitation Haematemesis Complications Oesophageal ulceration Peptic stricture Barrett’s oesophagus  Reflux Oesophagitis Treatment Antacids and alginates – available over-the-counter (OTC), often self-medicated before consultation. Prescribed in mild cases. H2-receptor antagonists – some available OTC, often self-medicated if antacids fail. Proton pump inhibitors – prescribed drugs of choice for all but mild cases.  NSAIDs impair renewal of the gastric mucosal barrier by interfering with prostaglandin production Prostaglandin E2 stimulates and support renewal of the gastric mucosal barrier by: stimulating gastric mucus production stimulating bicarbonate secretion inhibiting gastric acid production promoting local stomach tissue repair NSAIDs interfere with prostaglandin production (by inhibiting cyclooxygenase (COX)enzymes – more details in Block 3). thereby impair renewal of the gastric mucosal barrier. Impaired gastroprotection can result in gastric erosions, thereby causing or worsening ulcers.  ? What are Prostaglandins? A group of lipids (eicosanoids) derived from arachidonic acid. Made at sites of tissue damage or infection. Can be made in nearly all the organs in the body. Involved in healing processes, also inflammation and blood flow. Major step of prostaglandin synthesis is catalysed by a cyclooxygenase enzyme (COX). NSAIDs Inhibit Prostaglandin Synthesis – more in the Block 3 Analgesics lecture…. 3. Helicobacter Pylori infection A spiral-shaped Gram-negative bacterium, which damages stomach and duodenal tissue. Produces and secretes urease, which breaks down urea into CO2 and NH3. NH3 neutralises gastric acid. H. pylori penetrates mucus barrier, facilitating acid penetration. NH3, other bacterial products, and acid damage epithelial cells.  Treatment of H. Pylori Infection Treatment includes antibiotics (e.g. Amoxicillin with Clarithromycin – more on antibiotics in Block 4) and a proton pump inhibitor such as Lansoprazole. The eradication of H. pylori can produce long-term remission of ulcers.  Resources “Medical Pharmacology & Therapeutics” 6th Edition - Waller & Sampson; Chapter 33 – available via ClinicalKey Student “Rang & Dale’s Pharmacology” 10th Edition; Chapter 30 - available via ClinicalKey Student Some useful insights on using Proton Pump Inhibitors from the British National Formulary (BNF): https://bnf.nice.org.uk/treatment-summaries/proton-pump-in hibitors/