GI Drugs

1. GI Drugs PHC 5409B Dr. T.C. Peterson

2. Drugs for GI Tract disorders • DRUGS THAT REDUCE GASTRIC ACIDITY • CYTOPROTECTIVE DRUGS • DRUGS FOR HELICOBACTER PYLORI INFECTION • DRUGS FOR INFLAMMATORY BOWEL DISEASES • PROKINETIC DRUGS • LAXATIVES • ANTIDIARRHEAL AGENTS • ANTIEMETICS

3. Peptic Ulcer disease • Characterized by inflamed lesions and ulcers • Causes: • Excessive acid production • Bile acid reflux • Advancing age • Ischemia • Inhibition of PG synthesis • Infection with Helicobacter pylori

4. Drugs that reduce gastric acidity • H2 receptor antagonists • Proton pump inhibitors • Muscarinic antagonists • Prostaglandins • Antacids • Sucralfate

5. Cytoprotective Drugs • Sucralfate • Misoprostol

6. Drugs for H.pylori infection • Multi-drug therapy is usually used • Common combination: Gastric acid secretion inhibitor (PPI or H2 blocker) and two of the following: Amoxicillin, Bismuth, Clarithromycin, Metronidazole, Tetracycline

7. Inflammatory Bowel Disease Chronic Inflammatory disease: • Crohn's Disease (CD)  - full thickness inflammation anywhere in gastrointestinal tract • Ulcerative Colitis (UC) - inflammation of superficial layers, continuous from rectum • Lymphocytic Colitis - collections of lymphocytes without granulomas • Collagenous Colitis - collagenous deposition in subepithelial zone, rectum and colon Diagnosis is clinical but requires tissue biopsy for confirmation and classification

8. IBD  -  Treatment   • Acute Moderate to Severe Exacerbation - Usually in patients with known disease, now active • Glucocorticoids • Broad spectrum antibiotics (including metronidazole) • Intravenous cyclosporine may be used after 7-10 days if responses are poor • Chronic Therapy (Remission Maintenance)    • 5-aminosalicylate (5-ASA) • Azathioprine, 6-mercaptopurine (6-MP) and methotrexate

9. IBD drugs • Sulfasalazine • First line therapy in most patients with acute or chronic IBD • Congener of sulfapyridine and 5-aminosalicylic acid linked by an azo bond • Attenuates inflammation in the large bowel only • Compound is cleaved to composite groups by colonic bacteria (azoreductase) • Requires 5-28 days for efficacy • Contradindicated in patients with sulfa allergy; 15% of patients will discontinue drug • Side effects: cytopenias, pancreatitis, hepatitis, rash, diarrhea, male infertility

10. IBD drugs • Olsalazine • Dimer of 5-ASA linked by azo bond which is split by colonic bacteria • Contraindicated in patients with salicylate allergy; no sulfa moiety • Main side effect is diarrhea (~25% of patients) • Main use is in patients who cannot tolerate sulfasalazine • Appears to be as effective as sulfasalazine for mild to moderate IBD

11. IBD drugs • Mesalamine • Delayed release 5-ASA (ie. coated with acrylic-based resin) dissolves at pH 6 • Mainly released in distal ileum and colon;

12. IBD drugs • Azathioprine • Side Effects: Pancreatitis (~5%), Bone marrow suppression (~2%), hepatitis • Mildly effective as single agent, does prevent flares of disease and maintain remissions • Usually permits reduction in glucocorticoid dose required for suppression of disease • Note: this drug is metabolized to 6-MP

13. IBD drugs • 6-Mercaptopurine (6-MP) • Effective in prevention of relapses and possibly in active disease • Most patients require >17 weeks to see initial effect • 6-MP and AZA are effective in 50-70% of patients with IBD • Side effects include bone marrow suppression and pancreatitis, hepatitis

14. IBD drugs • Methotrexate • 20-25mg/week given i.m. in refractory Crohn's disease disease • Extremely well tolerated • Allowing lowering of steroid doses and control of disease • Recommended now in nearly all patients requiring higher dose prednisone

15. IBD drug • Cyclosporine • Good response initially to iv form, usually within 48 hours • Relapses common when drug is stopped • This agent shows most rapid onset of activity in steroid refractory disease • Reduces need for surgical resection in fulminant UC • Dose must be monitored closely

16. Novel Therapies for IBD • Specific Cytokine Blockers • IL-1 receptor antagonist (IL-1RA) • TNFa blockers • Other immunosuppressive agents may be effective • Cyclosporine • Rapamycin • FK506 and other immunosuppressives • Fish Oil (EPA) • May reduce production of inflammatory leukotrienes and thromboxanes • Suppresses IL-1 and TNF production • Reduced CD exacerbations at 1 year

17. IBD drugs • Tumor Necrosis Factor Alpha (TNFa) Blockade • Activity predicted on the basis of certain animal models • Has good activity in Crohn's Disease, including fistula healing

18. Prokinetic Drugs • Drugs used to increase GI motility • Increase activity of smooth muscle in the esophagus, stomach and intestine • examples: • Cisapride: stimulates 5-HT receptors • Metoclopramide: blocks dopamine D2 receptors

19. Antidiarrheal Agents • Bismuth subsalicylate, diphenoxylate, kaolin-pectin, loperamide, and polycarbophil • Opioid Drugs

20. Antiemetic drugs • Dopamine D2 receptor antagonists • Serotonin 5HT3 receptor antagonists • Other antiemetics • Dimenhydrinate and scopolamine

21. Review of drugs for GI Disorders • DRUGS THAT REDUCE GASTRIC ACIDITY Histamine 2 receptor antagonists • Cimetidine, famotidine, and ranitidine Proton pump inhibitors Lansoprazole and omeprazole Muscarinic receptor antagonists • Atropine and pirenzepine Gastric antacids Aluminum and magnesium hydroxides and calcium carbonate

22. Review of drugs for GI Disorders Cytoprotective drugs Misoprostol and sucralfate Drugs for Helicobacter pylori infection • Amoxicillin, bismuth, clarithromycin, metronidazole, and tetracycline • DRUGS FOR INFLAMMATORY BOWEL DISEASES • .Azathioprine, infliximab, mercaptopurine, mesalamine, metronidazole, prednisolone, and sulfasalazine

23. Review of drugs for GI Disorders • PROKINETIC DRUGS • Cisapride and metoclopramide • ANTIDIARRHEAL AGENTS • Bismuth subsalicylate, diphenoxylate, kaolin-pectin, loperamide, and opiates • ANTIEMETICS Serotonin 5-HT3 receptor antagonists • Granisetron and ondansetron Dopamine D2receptor antagonists • Metoclopramide