Drugs used in GIT disorders

1. Drugs used in GIT disorders HaithamAlwali Ph.D. Pharmacology Al-Nahrain College of Medicine Haitham Alwali

2. Haitham Alwali

3. A. Drugs Used in Acid-Peptic Diseases • Ulceration and erosion of the lining of the upper portion ofthe gastrointestinal tract are common problems that manifest asgastroesophagealreflux disease (GERD), gastric and duodenalpeptic ulcers, and stress-related mucosal injury. • Drugs used inacid-peptic disease reduce intragastric acidity by manipulatingsystems controlling acid secretion, promote mucosaldefense or, in the case of peptic ulcers, eradicate the bacteriumHelicobacter pylori, which is detectable in over 80% of patientswith duodenal ulcers. Haitham Alwali

4. 1. Antacids:are weak bases that neutralize stomach acid by reacting with protons in the lumen of the gut and may alsostimulate the protective functions of the gastric mucosa. antacids reduce the recurrence rate of peptic ulcers. • Popular antacids include magnesium hydroxide(Mg[OH]2) and aluminum hydroxide (Al[OH]3). Neither of theseweak bases is significantly absorbed from the bowel. Magnesiumhydroxide has a strong laxativeeffect, whereas aluminum hydroxidehas a constipating action. These drugs are available as single-ingredientproducts and as combined preparations. Haitham Alwali

5. Calcium carbonateand sodium bicarbonate are also weak bases, but they differ fromaluminum and magnesium hydroxides in being absorbed from thegut. Because of their systemic effects, calcium and bicarbonate saltsare less popular as antacids. 2. H2-receptor antagonists—Cimetidine and otherH2 antagonists(ranitidine, famotidine, and nizatidine) inhibit stomachacid production, especially at night. They are effective in thetreatment of GERD, peptic ulcer disease, and nonulcerdyspepsiaand in the prevention of stress-related gastritis. Haitham Alwali

6. 3. Proton pump inhibitors—Omeprazole and (esomeprazole, (dex)lansoprazole, pantoprazole, andrabeprazole) are lipophilic weak bases that diffuse into theparietal cell canaliculi, where they becomeprotonated and concentratedmore than 1000-fold. There they undergo conversionto compounds that irreversibly inactivate the parietal cell H+/K+ATPase, the transporter that is primarily responsible for producingstomach acid. Haitham Alwali

7. Oral formulations of these drugs are entericcoated to prevent acid inactivation in the stomach. After absorptionin the intestine, they are rapidly metabolized in the liver, withhalf-lives of 1–2 h. However, their durations of action areapproximately24 h, and they may require 3–4 d of treatment to achievetheir full effectiveness. Proton pump inhibitors are more effective than H2 antagonistsfor GERD and peptic ulcer and equally effective in the treatmentof nonulcer dyspepsia and the prevention of stress-related mucosalbleeding. They are also useful in the treatment of Zollinger-Ellison syndrome. Haitham Alwali

8. Adverse effects of proton pump inhibitors • occur infrequently and include diarrhea, abdominalpain, andheadache. Chronic treatment with proton pump inhibitors mayresult in hypergastrinemia. • Proton pump inhibitors may decrease the oral bioavailabilityof vitamin B12 and certain drugs that require acidityfor their gastrointestinal absorption (eg, digoxin, ketoconazole). • Patients taking proton pump inhibitors may have a small increasein the risk of respiratory and enteric infections. Haitham Alwali

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10. 4. Sucralfate—An aluminum sucrose sulfate, sucralfateis a small, poorly soluble molecule that polymerizes in the acid environment of the stomach. The polymer binds to injured tissue and forms a protective coating over ulcer beds. Sucralfateaccelerates the healing of peptic ulcers and reduces the recurrence rate. 5. Misoprostol—An analog of PGE1, misoprostol increases mucosal protection and inhibits acid secretion. It is effective in reducing the risk of ulcers in users of non steroidal anti-inflammatory drugs (NSAIDs). Haitham Alwali

11. 6. Antibiotics—Chronic infection with H pylori is present in most patients with recurrent non-NSAID-induced peptic ulcers. Eradication of this organism greatly reduces the rate of recurrence of ulcer in these patients. One regimen of choice consists of a proton pump inhibitor plus a course of clarithromycin and amoxicillin (or metronidazole in patients with penicillin allergy). Haitham Alwali

12. B. Drugs That Promote Upper Gastrointestinal Motility • Their ability to increase lower esophageal sphincter pressures also makes them useful for some patients with GERD. • In the enteric nervous system, dopamine inhibits cholinergic stimulation of smooth muscle contraction. Metoclopramideand domperidoneare D2 dopamine receptor antagonists that promote gastrointestinal motility. • When used chronically, metoclopramide can cause symptoms of parkinsonism, other extrapyramidal effects, and hyperprolactinemia. Because it does not cross the blood-brain barrier, domperidone is less likely to cause CNS toxicity. • The macrolide antibiotic erythromycinpromotes motility by stimulating motilin receptors. Haitham Alwali

13. C. Laxatives: Mechanism Examples 1-Bulk-formingPsyllium, methylcellulose 2-Stool-softening glycerin, mineral oil 3-Osmotic Magnesium oxide, lactulose, 4-Stimulant Aloe, senna, cascara, castor oil, bisacodyl 5-Chloride channel Lubiprostone activator Haitham Alwali

14. D. Antidiarrheal Agents Diphenoxylateand loperamide, meperidine analogs with very weak analgesic effects. Diphenoxylateis formulated with antimuscarinic alkaloids (eg, atropine) to reduce the likelihood of abuse; loperamideis formulated alone. Kaolin, a naturally occurring hydrated magnesium aluminum silicate, is combined with pectin, an indigestible carbohydrate derived from apples ( absorbs bacterial toxins and fluid, resulting in decreased stool liquidity. these agents should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition. Haitham Alwali

15. E. Drugs Used for Irritable Bowel Syndrome(IBS) is associated with recurrent episodes of abdominal discomfort (pain, bloating, distention, or cramps) plus diarrhea or constipation (or both). • The pharmacologic strategy includes antidiarrheal agents OR laxatives; and for the treatment of abdominal pain, low doses of tricyclic antidepressants • dicyclomine and hyoscyamineare used as antispasmodics to relieve abdominal pain • Alosetron, a potent 5-HT3 antagonist, is approved for treatment of women with severe IBS with diarrhea. • Lubiprostone, a laxative that activates the type 2 chloride channels in the small intestine. Haitham Alwali

16. F. Drugs With Antiemetic Actions • In addition to metoclopramide and other D2 dopamine receptor antagonists, useful antiemetics are drugs with H1 histamine blocking activity (diphenhydramine), and several phenothiazines; antimuscarinic drugs such as scopolamine; the corticosteroid dexamethasone ; and the cannabinoid receptor agonists dronabinol. • The 5-HT3 antagonists ondansetron, granisetron, dolasetronare useful in preventing nausea and vomiting after general anesthesia and in patients receiving cancer chemotherapy. • Aprepitant, a newer antiemetic, is an antagonist of the neurokinin1 (NK1) receptor, a receptor in the CNS that is activated by substance P and other tachykinins. Haitham Alwali

17. G. Drugs Used in Inflammatory Bowel Disease (IBD) • Aminosalicylates—Drugs containing 5 aminosalicylic acid (5-ASA) are used as topical therapy for IBD. The precise mechanism of 5-ASA action is uncertain but may involve inhibiting the synthesis of prostaglandins and inflammatory leukotrienes. Balsalazideand sulfasalazine (a combination of 5-ASA and sulfapyridine) has a higher incidence of adverse effects (sulfapyridine moiety) include gastrointestinal upset, headaches, arthralgias, bone marrow suppression, and severe hypersensitivity reactions 2. Other agents: includeantibiotics, glucocorticoids (budesonide), immunosuppressive antimetabolites (eg, azathioprine, methotrexate) antitumor necrosis factor [TNF] drugs (eg, infliximab, adalimumab). Haitham Alwali

18. H. Pancreatic Enzyme Replacements: Steatorrhea, a condition of decreased fat absorption together with an increase in stool fat excretion, results from inadequate pancreatic secretion of lipase. • The abnormality of fat absorption can be significantly relieved by oral administration of pancreatic lipase (pancrelipaseor pancreatin) obtained from pigs. • Pancreatic lipase is inactivated at a pH lower than 4.0; the enzyme should be taken as enteric-coated capsules. I. Drugs That Inhibit the Formation of Gallstones The formation of cholesterol gallstones can be inhibited by the bile acid derivative ursodiol, which decreases the cholesterol content of bile by decreasing hepatic cholesterol secretion. Haitham Alwali