Gastrointestinal drugs - Pharmacology
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The document discusses drugs used to treat peptic ulcers, gastroesophageal reflux disease, diarrhea, and constipation. It describes the causes of peptic ulcers including H. pylori infection and NSAID use. Treatment involves eradicating H. pylori, reducing gastric acid with H2 blockers or proton pump inhibitors, and protecting the gastric mucosa. Various classes of drugs are covered that act on these mechanisms including antimicrobials, H2 blockers, proton pump inhibitors, prostaglandins, and antacids.
Gastrointestinal drugs - Pharmacology
- 3. Drugs used for: 1) Peptic ulcers and gastroesophageal reflux disease (GERD) 2) Chemotherapy-induced emesis 3) Diarrhea 4) Constipation
- 4. Causes of peptic ulcer: Infection with gram-negative Helicobacter pylori Use of nonsteroidal anti-inflammatory drugs (NSAIDs) Increased hydrochloric acid secretion Inadequate mucosal defense against gastric acid Tumors (rare)
- 5. Treatment of peptic ulcer 1) Eradicating the H. pylori infection 2) Reducing secretion of gastric acid with the use of proton pump inhibitors or H2-receptor antagonists 3) Providing agents that protect the gastric mucosa from damage such as misoprostol and sucralfate 4) Neutralizing gastric acid with nonabsorbable antacids
- 6. Antimicrobials H2-receptor antagonists Proton pump inhibitors Prostaglandins Antacids
- 7. Antimicrobial agents (For H. pylori) ◦ Metronidazole ◦ Amoxicillin ◦ Clarithromycin ◦ Tetracyclines ◦ Bismuth compounds
- 8. Optimal therapy for patients with peptic ulcer disease infected with H. pylori requires antimicrobial treatment Endoscopic biopsy of the gastric mucosa or various noninvasive methods are used, including serologic tests and urea breath tests to document infection with H. pylori Eradication of H. pylori results in rapid healing of active peptic ulcers and low recurrence rates
- 10. GERD is not associated with H. pylori infection and does not respond to treatment with antibiotics Triple therapy consisting of a PPI combined with either metronidazole or amoxicillin plus clarithromycin for 2 weeks ◦ (Amoxicillin, omeprazole, clarithromycin) Peptipac®, Triopac® Quadruple therapy of bismuth subsalicylate and metronidazole plus tetracycline plus a PPI, administered for a 2-week course Treatment with a single antimicrobial drug is less effective, results in antimicrobial resistance, and is absolutely not recommended Switching antibiotics is not recommended Bismuth salts inhibit pepsin and increase the secretion of mucus
- 11. Ranitidine (Zantac®, Randin®, Ratidine®, GI-care®) Famotidine (Famodin®, Famo®, Gastrex®) Cimetidine (Cemidin®, Cimetag®, Tagamet®) Nizatidine
- 12. Gastric acid secretion by parietal cells of the gastric mucosa is stimulated by acetylcholine, histamine, and gastrin The receptor-mediated binding of acetylcholine, histamine, or gastrin results in the activation of protein kinases, which stimulates the H+/K+–adenosine triphosphatase (ATPase) proton pump to secrete hydrogen ions in exchange for K+ into the lumen of the stomach Receptor binding of prostaglandin E2 and somatostatin diminish gastric acid production Histamine binding causes activation of adenylyl cyclase, whereas binding of prostaglandin E2 inhibits it Gastrin and acetylcholine act by inducing an increase in intracellular calcium levels
- 13. Antagonists of the histamine H2 receptor are used to inhibit gastric acid secretion By competitively blocking the binding of histamine to H2 receptors, these agents reduce the intracellular concentrations of cAMP and, secretion of gastric acid Inhibit basal, food-stimulated, and nocturnal secretion of gastric acid after a single dose Cimetidine use is limited by its adverse effects and drug–drug interactions
- 15. Peptic ulcer Acute stress ulcers Gastroesophageal reflux disease (GERD)
- 16. Peptic ulcers: Effective in promoting the healing of duodenal and gastric ulcers Recurrence is common after treatment with H2 antagonists is stopped Patients with NSAID-induced ulcers should be treated with PPIs, because these agents heal and prevent future ulcers better than H2 antagonists
- 17. Acute stress ulcers H2 blockers are given as intravenous infusion to prevent and manage acute stress ulcers associated with high-risk patients in intensive care units PPIs have gained favor for this indication because tolerance may occur with these agents in this setting
- 18. GERD: Low doses of H2 antagonists is used for the prevention and treatment of heartburn (GERD) H2-receptor antagonists act by stopping acid secretion and may not relieve symptoms for at least 45 minutes Antacids more quickly and efficiently neutralize secreted acid in the stomach, their action is temporary PPIs are now used preferentially in the treatment of GERD
- 19. The dosage of all these drugs must be decreased in patients with hepatic or renal failure Cimetidine inhibits CYP450 leading to many interactions
- 20. Adverse effects: ◦ Headache ◦ Dizziness ◦ Diarrhea ◦ Muscular pain ◦ Cimetidine can also have endocrine effects because it acts as a nonsteroidal antiandrogen These effects include gynecomastia, and galactorrhea Drugs such as ketoconazole, which depend on an acidic medium for gastric absorption, may not be efficiently absorbed if taken with H2 blockers
- 21. Omeprazole (Locid®, Losec®, Marial®, Mepral®, Pepticum®) Esomeprazole (Nexium®, Ezomax®) Lansoprazole (Lanso®, Lanton®, Zoton®) Pantoprazole (Pantover®, Controloc®)
- 22. Bind to the H+/K+-ATPase enzyme system (proton pump) of the parietal cell and suppress the secretion of hydrogen ions into the gastric lumen, inhibiting gastric acid secretion The membrane-bound proton pump is the final step in the secretion of gastric acid More effective than H2 antagonists in suppressing gastric acid production and healing peptic ulcers
- 23. PPIs are prodrugs with an acid-resistant enteric coating to protect them from premature degradation by gastric acid The coating is removed in the duodenum, and the prodrug is absorbed and transported to parietal cells There, it is converted to the active form, which forms a stable covalent bond with H+/K+-ATPase It takes about 18 hours for the enzyme to be resynthesized At standard doses, all PPIs inhibit both basal and stimulated gastric acid secretion by ~90%
- 24. The superiority of the PPIs over the H2 antagonists for suppressing acid production and healing peptic ulcers has made them the preferred drugs for ◦ Stress ulcer treatment and prophylaxis ◦ Treating erosive esophagitis and active duodenal ulcer ◦ Long-term treatment of pathologic hypersecretory conditions (e.g. Zollinger-Ellison syndrome)
- 25. Approved for the treatment of GERD and have gained favor over H2 antagonists PPIs reduce the risk of bleeding from an ulcer caused by aspirin and other NSAIDs Used with antimicrobial regimens to eradicate H. pylori
- 26. PPIs should be taken 30 to 60 minutes before breakfast or the largest meal of the day If an H2-receptor antagonist is also needed, it should be taken well after the PPI for best effect because the H2 antagonists will reduce the activity of the proton pump In patients with GERD in whom a once-daily PPI is only partially effective, increasing to a twice-daily regimen or keeping the PPI in the morning and adding an H2 antagonist in the evening may improve symptom control
- 27. Diarrhea Clostridium difficile colitis • Patients must be counseled to discontinue PPI therapy if they have diarrhea for several days and to contact their physicians Possible increased risk of fractures of the hip, wrist, and spine • The greatest risk is associated with patients taking the PPIs for one year or greater
- 28. Drug interactions Decrease the effectiveness of clopidogrel due to inhibition of CYP2C19 • Increase risk of cardiovascular events Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and cyclosporine through competitive inhibition of CYP450 Prolonged therapy may result in low vitamin B12 Prolonged elevation of gastric pH can cause incomplete absorption of calcium carbonate products
- 29. Prostaglandin E, produced by the gastric mucosa, inhibits secretion of HCl and stimulates secretion of mucus and bicarbonate (cytoprotective effect) A deficiency of prostaglandins is involved in the pathogenesis of peptic ulcers
- 30. Misoprostol (Cytotec®) ◦ A stable analog of prostaglandin approved for the prevention of gastric ulcers induced by NSAIDs ◦ Less effective than H2 antagonists and the PPIs for acute treatment of peptic ulcers ◦ Has cytoprotective actions, but is clinically effective only at higher doses that diminish gastric acid secretion
- 31. Misoprostol ◦ Like other prostaglandins, misoprostol produces uterine contractions, dislodging of the fetus, and is contraindicated during pregnancy ◦ Adverse effects: diarrhea and nausea
- 32. Weak bases that react with gastric acid to form water and a salt to diminish gastric acidity Antacids also reduce pepsin activity because pepsin is inactive at a pH greater than 4
- 33. Aluminum hydroxide Magnesium hydroxide Calcium carbonate Systemic absorption of sodium bicarbonate can produce transient metabolic alkalosis and is not recommended for long-term use Food delays stomach emptying allowing more time for the antacid to react
- 34. Aluminum hydroxide + Magnesium hydroxide (Maalox®) Calcium carbonate + Magnesium carbonate (Rennie®) Calcium carbonate (Tums®)
- 35. Aluminum- and magnesium-containing antacids are used to: ◦ Provide symptomatic relief of peptic ulcer disease and GERD ◦ Promote healing of duodenal ulcers ◦ Used as last-line therapy for acute gastric ulcers Calcium carbonate preparations are also used as calcium supplements for the treatment of osteoporosis
- 36. Aluminum hydroxide causes constipation Magnesium hydroxide causes diarrhea The binding of phosphate by aluminum-containing antacids can lead to hypophosphatemia Sodium bicarbonate ◦ Can cause systemic alkalosis ◦ Liberates CO2, causing belching and flatulence ◦ The sodium content of antacids can be an important consideration in patients with hypertension or congestive heart failure
- 37. Cytoprotective compounds Enhance mucosal protection mechanisms, preventing mucosal injury, reducing inflammation, and healing existing ulcers. ◦ Sucralfate (Ulsanic®) ◦ Bismuth subsalicylate (Pink Bismuth®, Kalbeten®)
- 38. Bismuth subsalicylate Effectively heals peptic ulcers Has antimicrobial actions Inhibits the activity of pepsin Increases secretion of mucus, and interact with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer crater
- 39. Increased motility of GIT and decreased absorption of fluid are major factors in diarrhea Antidiarrheal drugs used to treat acute diarrhea include ◦ Antimotility agents ◦ Adsorbents ◦ Agents that modify fluid and electrolyte transport
- 40. Antimotility agents Diphenoxylate Loperamide (Diacare®, Imodium®) Both are analogs of meperidine and have opioid-like actions on the gut Activate presynaptic opioid receptors in the enteric nervous system to inhibit ACh release and decrease peristalsis Lack analgesic effects at usual doses Side effects: drowsiness, abdominal cramps, dizziness Contribute to toxic megacolon and should not be used in young children or in patients with severe colitis
- 41. Adsorbents Aluminum hydroxide Methylcellulose Used to control diarrhea Act by adsorbing intestinal toxins or microorganisms and/or by coating or protecting the intestinal mucosa Much less effective than antimotility agents and Can interfere with the absorption of other drugs
- 42. Agents that modify fluid and electrolyte transport Bismuth subsalicylate Used for traveler’s diarrhea Decreases fluid secretion in the bowel Its action may be due to its salicylate component as well as its coating action Adverse effects may include black tongue and black stools
- 43. Common condition caused by ◦ Diminished fluid intake ◦ Slow motility of waste material through large intestine ◦ Certain foods, medications, diseases
- 44. Irritants and stimulants Bulk laxatives Saline and osmotic laxatives Stool softeners (emollient laxatives or surfactants) Lubricant laxatives Chloride channel activators
- 45. Irritants and stimulants Senna Bisacodyl Castor oil
- 46. Saline and osmotic laxatives Magnesium citrate Magnesium hydroxide Sodium phosphate ◦ Nonabsorbable salts that hold water in the intestine by osmosis ◦ This distends the bowel, increasing intestinal activity and producing defecation in a few hours
- 47. Stool softeners (emollient laxatives or surfactants) Docusate sodium Docusate calcium Docusate potassium Surface-active agents that become emulsified with the stool produce softer feces and ease passage May take days to become effective and are often used for prophylaxis rather than acute treatment
- 48. Lubricant laxatives Include mineral oil and glycerin suppositories Act by facilitating the passage of hard stools Mineral oil should be taken orally in an upright position to avoid its aspiration and potential for lipid or lipoid pneumonia