Drugs Used in the Treatment of Gastrointestinal Diseases

1. Drugs Used in the Treatment of Gastrointestinal Diseases Drugs used in Peptic Ulcer Diseases. Drugs Stimulating Gastrointestinal Motility. Laxatives. Antidiarrheal Agents. Drugs used in Irritable Bowel Syndrome. Antiemetic Agents. Drugs used in Inflammatory Bowel Disease. Pancreatic Enzyme Supplements.

2. Agents that Reduce Intragastric Acidity Physiology of Acid Secretion The parietal cell contains receptors for gastrin CCK-B (gastrin-cholecystokinin-B receptors), histamine (H2), and ACH (muscarinic, M3). When ACH or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+-ATPase (the proton pump) on the canalicular (A small canal or duct ) surface.

3. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin -like (ECL) cells. ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intra-cellular cAMP and activates protein kinases that stimulate acid secretion by the H+/K+-ATPase. In humans, the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In contrast, acetylcholine provides potent direct parietal cell stimulation.

4. (gastrin-cholecystokinin-B receptors)

5. Antacids Nonprescription remedies for the treatment of heartburn and dyspepsia. Weak bases that react with gastric hydrochloric acid to form a salt and water. Given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. Efficacy varies according to rate of dissolution, water solubility, rate of reaction with acid and the rate of gastric emptying. May affect the absorption of other medications by binding to drugs or by changing ph, therefore, dissolution.

6. Sodium bicarbonate Reacts rapidly with HCL to produce carbon dioxide and sodium chloride. CO2 results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency.

7. Calcium carbonate Less soluble. Reacts more slowly to form carbon dioxide and calcium chloride (CaCl2). May cause belching or metabolic alkalosis. Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome: hypercalcemia caused by repeated ingestion of calcium and absorbable alkali (such as calcium carbonate, or milk and sodium bicarbonate).

8. Magnesium Hydroxide. Aluminum Hydroxide. React slowly and without gas formation. Metabolic alkalosis is also uncommon. Mg salts cause diarrhea. Aluminum salts cause constipation. Usually given in combination. Contraindicated in renal insufficiency.

9. H2-Receptor Antagonists Cimetidine, Ranitidine, Famotidine, and Nizatidine. Rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism, bioavailability 50%. Nizatidine has little first-pass metabolism. Duration of action:6–10 hours, given twice daily. Inhibit 90% of nocturnal acid (which depends largely on histamine). Have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin, acetylcholine and histamine). Inhibit 60% of day-time, meal stimulated, acid. Inhibit 60-70% of total 24-h acid secretion.

10. Clinical Uses of H2-Receptor Antagonists Gastroesophageal Reflux Disease (GERD) Taken prophylactically before meals. In patients with erosive esophagitis H2 antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred. Non Ulcer Dyspepsia. Over-the-counter agents for treatment of intermittent dyspepsia not caused by peptic ulcer. Prevention of Bleeding from Stress-Related Gastritis IV H2 antagonists are preferable over intravenous proton pump inhibitors because of their proven efficacy and lower cost. Continuous infusions of H2 antagonists are preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH.

11. Peptic Ulcer Disease: Replaced by PPI. Healing rate more than 80-90% after 6-8 weeks. Not effective in the presence of H. pyloriinfection H pylori should be treated with a 10- to 14-day course of a proton pump inhibitor and two antibiotics. If H pylori cannot be eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence. Not effective if NSAID is continued.

12. Adverse Effects: 1-Extremely safe drugs. Diarrhea, headache, fatigue, myalgias, and constipation (3% of patients) . 2-Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. 3- Long-term use may cause gynecomastia or impotence in men and galactorrhea in women 4- Crosses placental barrier and appear in breast milk

13. 5- Other Effects: Rarely can cause blood dyscrasias, bradycardia and hypotension. Mental status changes (confusion, agitation hallucinations,) may occur with intravenous H2 antagonists Drug Interactions: Cimetidine can inhibit cytochrome P450 enzymes so can increase half life of many drugs. Ranitidine binds 4-10 times less. Nizatidine and famotidine binding is negligible.

14. Proton Pump Inhibitors (PPIs) Among the most widely prescribed drugs worldwide due to their outstanding efficacy and safety. Omeprazole (oral). Rabeprazole (oral). Lanzoprazole (oral and IV). Pantoprazole (oral and IV). Esmoprazole (oral and IV). Formulated as a prodrugwhich is released in the intestine. Immediate Release Suspension (contains sodium bicarbonate to protect the drug from acid degradation) results in rapid response.

15. Pharmacokinetics: They are lipophilic weak bases (pKa 4-5). After absorption, they diffuse across lipid membranes into acidified compartments such as the parietal cell canaliculus. The prodrug becomes protonated and concentrated more than 1000-fold within the parietal cells. There, it undergoes a molecular conversion to the active form which covalently binds the H+/K+ ATPase enzyme and inactivates it. Rabeprazole and immediate release omeprazole have faster onsets of action. Should be given one hour before meal, usually breakfast.

16. Have short half lives but effect lasts for 24 hours due to irreversible inhibition. Inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion (90-98% of 24-hour secretion). At least 18 hours are required for synthesis of new H+/K+-ATPase pump molecules. Up to 3–4 days of daily medication are required before the full acid-inhibiting potential is reached.

17. Clinical Uses of (PPIs) : Gastroesophageal Reflux (GERD): They are the most effective agents in all forms of GERD and complications. Nonulcer Dyspepsia: Modest activity.10-20% more beneficial than a placebo Stress- Related Gastritis: Oral immediate- release omeprazole administered by nasogastric tube. For patients without a nasoenteric tube, IV H2-antagonists are preferred because of their proven efficacy. Gastrinoma and other Hypersecretory Conditions: Usually high doses of omeprazole are used.

18. Peptic Ulcer Disease: They heal more than 90% of cases within 4-6 weeks. H.Pylori - associated ulcers: PPI eradicate H.pylori by direct antimicrobial activity and by lowering MIC of the antibiotics. Triple Therapy: PPI twice daily + Clarithromycin 500mg twice daily +Amoxicillin 1gm twice daily ,OR, Metronidazole 500mg twice daily. NSAID-associated ulcers: PPIs promote ulcer healing despite continued NSAID use. Also used to prevent ulcer of NSAIDs Rebleeding peptic ulcer: Oral or IV. High pH may enhance coagulation and platelet aggregation.

19. Adverse Effects of PPIs: Diarrhea, headache, abdominal pain, not teratogenic in animals, but not used in pregnancy. Reduction of cyanocobalamine absorption. Increased risk of GI and pulmonary infection. Increased serum gastrin levels causes: Hyperplasia of ECL cells and Carcinoid tumors in rats but not in humans. Increase proliferative rate of colonic mucosa, but no cancer developed. Chronic inflammation in gastric body. Atrophic gastritis and intestinal metaplasia (the transformation of epithelium, usually of the stomach or the esophagus , to a type that bears some resemblance to the intestine )

20. Drug Interactions: May affect absorption of drugs due to decreased gastric acidity like digoxin and ketoconazole. Omeprazole can inhibit metabolism of coumadin (Warfarin ), diazepam and phenytoin. Rabeprazole and pantoprazole have no significant interaction.

21. Mucosal Protective Agents 1-Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. 2-Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1–2 in the gastric lumen. 3-Blood flow carries bicarbonate and vital nutrients to surface cells. 4-Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to reestablish intact epithelium. 5- Mucosal prostaglandins stimulates mucus and bicarbonate secretion and mucosal blood flow.

22. Sucralfate A salt of sucrose complexed to sulfated aluminum hydroxide. In the stomach, It breaks down into sucrose sulfate (strongly negatively charged) and an aluminum salt. The negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosion, forming a physical barrier that restricts further caustic damage and stimulates mucosal prostaglandin and bicarbonate secretion. Acts for up to 6 hours. Less than 3% of intact drug and aluminum is absorbed from GIT.

23. Clinical Uses 1 g four times daily on an empty stomach (administered as a slurry through a nasogastric tube) reduces the incidence of upper gastrointestinal bleeding in critically ill patients hospitalized in the intensive care unit. Used for prevention of stress-related bleeding because of concerns that acid inhibitory therapies (antacids, H2 antagonists, and proton pump inhibitors) may increase the risk of nosocomial pneumonia (an infection of the lungs that occurs during a hospital stay).

24. Adverse Effects Because it is not absorbed, sucralfate is virtually devoid of systemic adverse effects. Constipation occurs in 2% of patients due to the aluminum salt. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency. Drug Interactions Sucralfate may bind to other medications, impairing their absorption.

25. Prostaglandin Analogs Misoprostol, A methyl analog of PGE1. Half-life is less than 30 minutes; administered 3-4 times daily. It stimulates mucus and bicarbonate secretion and enhance mucosal blood flow. It binds to a prostaglandin receptor on parietal cells, reducing histamine-stimulated cAMP production and causing modest acid inhibition. Stimulates intestinal electrolyte & fluid secretion, intestinal motility and uterine contractions.

26. Clinical Uses of Prostaglandin Analogs: Prevention of NSAID-induced ulcers in high-risk patients. Not widely used for this purpose because of: a- side effects. b. need for multiple daily dosing. c. PPI may be as effective and better tolerated. d. Cyclooxygenase2-selective NSAIDs are an option for such patients. Adverse Effects & Drug Interactions Diarrhea and cramping abdominal pain occur in 10–20% of patients. it should not be used during pregnancy No significant drug interactions are reported.

27. Colloidal Bismuth Compounds: Bismuth subsalicylate. Bismuth subcitrate. Bismuth is minimally absorbed from GIT (< 1%). Coats ulcers and erosions, creating a protective layer against acid and pepsin. It may stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secretion. Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler's diarrhea. Have direct antimicrobial activity against H pylori.

28. Widely used for the nonspecific treatment of dyspepsia and acute diarrhea. Bismuth subsalicylate also is used for the prevention of traveler's diarrhea. Used as second-line therapy for the eradication of H pylori infection (a PPI with bismuth subsalicylate , tetracycline and metronidazole for 10–14 days). Adverse Effects Causes blackening of the stool and the tongue. Prolonged usage may rarely lead to bismuth toxicity, resulting in encephalopathy.

29. Drugs Stimulating Gastrointestinal Motility (prokineticagents) Agents that increase lower esophageal sphincter pressures may be useful for GERD. Drugs that improve gastric emptying may be helpful for gastroparesis and postsurgical gastric emptying delay. Agents that stimulate the small intestine may be beneficial for postoperative ileus or chronic intestinal pseudo-obstruction. Agents that enhance colonic transit may be useful in the treatment of constipation.

30. Physiology of the Enteric Nervous System The ENT is composed of interconnected networks of ganglion cells and nerve fibers mainly located in the submucosa (submucosal plexus) and between the circular and longitudinal muscle layers (myentericplexus). Extrinsic sympathetic and parasympathetic nerves project onto the submucosal and myenteric plexuses. The enteric nervous system can independently regulate gastrointestinal motility and secretion. Extrinsic primary afferent neurons project via the dorsal root ganglia or vagus nerve to the CNS.

31. Release of serotonin (5-HT) from intestinal mucosa enterochromaffin (EC) cells stimulates 5-HT3 receptors on the extrinsic afferent nerves, stimulating nausea, vomiting, or abdominal pain. Serotonin also stimulates submucosal 5-HT1P receptors of the intrinsic primary afferentnerves (IPANs).

32. IPANs) contain calcitoningene-related peptide (CGRP) and acetylcholine and project to myenteric plexus interneurons. 5-HT4 receptors on the presynaptic terminals of the IPANs enhance release of CGRP or Ach. The myenteric interneurons control: peristaltic reflex, promoting release of excitatory mediators proximally and inhibitory mediators distally. Motilin may stimulate excitatory neurons or muscle cells directly. Dopamine acts as an inhibitory neurotransmitter in the GIT, decreasing the intensity of esophageal and gastric contractions.

33. Figure 62–4  Release of serotonin (5-HT) by enterochromaffin (EC) cells from gut distention stimulates submucosal intrinsic primary afferent neurons (IPANs) via 5-HT1P receptors and extrinsic primary afferent neurons via 5-HT3 receptors (5-HT1PR, 5-HT3R). Submucosal IPANs activate the enteric neurons responsible for peristaltic and secretory reflex activity. Stimulation of 5-HT4 receptors (5-HT4R) on presynaptic terminals of IPANs enhances release of acetylcholine (ACh) and calcitoningene-related peptide (CGRP), promoting reflex activity. CNS, central nervous system; ENS, enteric nervous system.

34. Cholinomimetic Agents Bethanechol Stimulates muscarinic M3 receptors on muscle cells and at myenteric plexus synapses . Was used for the treatment of GERD and gastroparesis. Neostigmine AchE inhibitor can enhance gastric, small intestine, and colonic emptying. IV neostigmine used for the treatment of acute large bowel distention (acute colonic pseudo-obstruction). Administration of 2 mg results in prompt colonic evacuation of flatus and feces. Cholinergic effects include excessive salivation, nausea, vomiting, diarrhea, and bradycardia.

35. Dopamine D2-receptor antagonists. Metoclopramide & Domperidone D2 Antagonists. DA inhibits cholinergic smooth muscle stimulation. These agents: -increase esophageal peristaltic amplitude. -increase lower esophageal sphincter pressure. -enhance gastric emptying. -have no effect on small intestine or colonic motility. Also block dopamine D2 receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action.

36. Clinical Uses Gastroesophageal Reflux Disease Not effective with erosive esophagitis. Not superior to antisecretory agents. Used mainly in combination with antisecretory agents in patients with refractory heartburn. Impaired Gastric Emptying (Gastroparesis) widely used in the treatment of postsurgical and diabetic gastroparesis. Metoclopramide is used to promote advancement of nasoenteric feeding tubes from the stomach into the duodenum. Nonulcer Dyspepsia Prevention of Vomiting Postpartum Lactation Stimulation Domperidone is used to promote postpartum lactation

37. Adverse Effects: Metclopromidecrosses BBB so can cause: Restlessness, drowsiness, insomnia, anxiety, agitation, extrapyramidal symptoms (dystonia, akathisia, parkinsonian features) and tardive dyskinesia. Domperidonedoes not cross the BBB, so does not cause CNS effects Both drugs can elevate serum prolactin levels causing galactorrhea, gynecomastia, impotenceand menstrual disorders.

38. Laxatives Intermittent constipation is best prevented with a high-fiber diet, adequate fluid intake, regular exercise, and responding to nature's call. Bulk-Forming Laxatives Indigestible, hydrophilic colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. Common preparations include natural plant products (psyllium, methylcellulose) and synthetic fibers (polycarbophil). Bacterial digestion of plant fibers within the colon may lead to increased bloating and flatus.

39. Stool Surfactant Agents (Softeners) Soften stool material, permitting water and lipids to penetrate. Administered orally or rectally. Docusate (oral or enema) and glycerin suppository. Mineral oil Clear, viscous oil that lubricates fecal material, retarding water absorption from the stool. Used to prevent and treat fecal impaction. Aspiration can result in a severe lipid pneumonitis Long-term use can impair absorption of fat-soluble vitamins.

40. Osmotic Laxatives Soluble but nonabsorbable compounds that result in increased stool liquidity due to an increase in fecal fluid. Nonabsorbable Sugars or Salts Used for the treatment of acute constipation or the prevention of chronic constipation. Magnesium hydroxide (milk of magnesia) Not used for prolonged periods in patients with renal insufficiency due to the risk of hypermagnesemia. Large doses of magnesium citrate and sodium phosphate can cause Purgation: rapid bowel evacuation within1-3 hours. This might cause volume depletion.

41. Sorbitol, Lactulose Sugars metabolized by bacteria producing severe flatus and cramps. Balanced Polyethylene Glycol: PEG is an inert, nonabsorbable, osmotically active sugar with sodium sulfate, sodium chloride, sodium bicarbonate, and potassium chloride. Safe, no intrvascular fluid or electrolyte shifts. No cramps or flatus. Used for complete colonic cleansing before endoscopy For colonic cleansing, it should be ingested rapidly( 4 L over 2-4hs). For chronic constipation, PEG powder is mixed with water or juice.

42. Stimulant Laxatives Direct stimulation of the enteric nervous system and colonic electrolyte and fluid secretion. Anthraquinone Derivatives: Aloe, senna, and cascara Occur naturally in plants. Poorly absorbed and after hydrolysis in the colon, produce a bowel movement in 6–12 hours when given orally and within 2 hours when given rectally. Chronic use leads to a brown pigmentation of the colon known as "melanosis coli.“ Not carcinogenic.

43. Bisacodyl Tablet and suppository for treatment of acute and chronic constipation. It also is used in conjunction with PEG solutions for colonic cleansing prior to colonoscopy. It induces a bowel movement within 6–10 hours when given orally and 30–60 minutes when taken rectally. Safe for acute and long-term use. Phenolphthalein Removed from the market owing to concerns about possible cardiac toxicity

44. Opioid Receptor Antagonists Do not cross the blood-brain barrier. Block peripheral (µ) mu -opioid receptors without causing central analgesic effects. Methylnaltrexone Used for opioid- induced constipation in patients with advanced illness not responding to other agents. Given by S.C. injection every 2 days. Alvimopan Short-term use for postoperative ileus in hospitalized patients. Given orally within 5 hours before surgery and twice daily after surgery until bowel function has recovered, but for no more than 7 days, because of possible cardiovascular toxicity.

45. Antidiarrheal Agents Should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition. Used to control chronic diarrhea caused by irritable bowel syndrome (IBS) or inflammatory bowel disease.

46. Opioid Agonists Inhibit presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements CNS effects and potential for addiction limit the usefulness of most. Loperamide Does not cross BBB. No analgesic or addiction potential. Diphenoxylate Not analgesic in standard doses. Higher doses have CNS effects. Can cause dependence. Commercial preparations contain small amounts of atropine which contribute to the antidiarrheal action.

47. Bile Salt-Binding Resins Cholestyramine Colestipol Colesevelam Malabsorption of bile salts (e. g . Crohn's disease or after surgical resection), can cause diarrhea. The drugs can bind bile salts and decrease diarrhea caused by excess fecal bile acids. Can cause bloating, flatulence, constipation and fecal impaction. Cholestyramine and colestipol reduce absorption of drugs and fat. Colesevelam have no effects on absorption of other drugs.

48. Octreotide: Is a synthetic octapeptide with actions similar to somatostatin. Somatostatin A14 amino acid peptide released in the GIT and pancreas as well as from the hypothalamus: 1. Inhibits release of many hormones. 2. Reduces intestinal fluid and pancreatic secretions. 3. Slows GIT motility and gallbladder contraction. 4. Contracts blood vessels. 5. Inhibits secretion of some anterior pituitary hormones.

49. Clinical Uses: 1. Inhibition of endocrine tumor effects: Carcinoid and VIPoma (neuroendocrine tumors that secrete vasoactive intestinal polypeptide (VIP) ) can cause secretory diarrhea, flushing and wheezing. 2. Diarrhea due to vagotomy or dumping syndrome (ingested foods bypass the stomach too rapidly) or short bowel syndrome and AIDS. 3. To stimulate motility in small bowel bacterial overgrowth or intestinal pseudo-obstruction secondary to scleroderma (a disease affecting the skin and other organs that is one of the autoimmune rheumatic diseases).

50. 4- Because it inhibits pancreatic secretion, it is used in patients with pancreatic fistula (leakage of pancreatic secretions from damaged pancreatic ducts ). 5- treatment of pituitary tumors (e.g., acromegaly) 6- Sometimes used in gastrointestinal bleeding. Adverse Effects: Impaired pancreatic secretion may cause steatorrhea (the presence of excess fat in feces ), which can lead to fat-soluble vitamin deficiency. Nausea, abdominal pain, flatulence, and diarrhea. Formation of sludge or gallstones, because of inhibition of gallbladder contractility and fat absorption. Hyper or hypoglycemia due to hormonal imbalance. Hypothyroidism. Bradycardia.