Gastro Intestine tract pharmacology 2013 B.pptx

Pharmacology of gastrointestinal tract agents for third year pharmacy student

1. Gastrointestinal Drugs 1

2. Objectives: At the end of this unit, you will be able to: Discuss drugs acting on gastro intestinal tract Explain the mechanism of action, adverse effects and contraindications of drugs used for Peptic Ulcers, Constipation, Diarrhea Vomiting 2

3. The Gastrointestinal Tract 3

4. Introduction to GIT Main functions of the GIT are Gastric secretions Release of acid Breakdown of food staffs Vomiting → removal of toxic substances accidentally ingested. Motility and absorption of food Liver is important for the formation and release of bile into GIT important for absorption of fat. 4

5. Stomach... Glandular compartment Cardia glands contain mucus secreting cells only Oxyntic ( fundic ) glands contain parietal cells, chief cells and endocrine cells Parietal cells possess the H + -K + -ATPase that pumps out H + in exchange for K + Chief cells secrete pepsinogen I and II Anthral or pyloric glands contain mucus-secreting cells and endocrine cells Endocrine cells secrete, endocrinally or paracrinally , such chemicals as Gastrin (G-cells in antrum ), Histamine (in the body), Somatostatin (D-cells), Endothelin (x-cells) 5

6. Stomach 6

7. Intro.. Physiologic activator and inhibitors of gastric acid secretion include Gastrin Acetylcholine Histamine Prostaglandin somatostatin 7

8. Activators of proton pump Acetylcholine stimulates M 3 Ach- Rs resulting in increase in cytosolic Ca ++ in parietal cells Gastrin activates gastrin Rs , resulting in increase in cytosolic Ca ++ in parietal cells Ach and Gastrin activate release of Histamine from Enterochromaffin -like cells (ECL) which stimulates H 2 Receptors on parietal cells (the main pathway of proton pump activation) 8

9. Inhibitors of proton pump Somatostatin through somatostatin receptors Prostaglandins (Prostaglandins of the A, E, and I type inhibit gastric acid secretion, stimulate increased mucus and bicarbonate secretion by gastric mucosa) Epidermal growth factor 9

10. Mucosal protection Mechanisms that protect the gastric mucosa from autodigestion of gastric acidity and peptic enzymes Mucus secretion Bicarbonate secretion (surface epithelial cells) Epithelial barrier Mucosal blood flow Prostaglandin synthesis Favour production of mucus and bicarbonate Inhibit acid secretion by parietal cells PGE and PGI improve mucosal blood flow 10

11. GASTROINTESTINAL DISORDERS Gastroesophageal Reflux Disease (GERD) Peptic Ulcer Disease (PUD) Duodenal Ulcer Nausea Emesis IBS Diarrhea Constipation 11

12. 12

13. 1.Drugs Used to Treat PUD and GERD What is GERD? GERD is when acid and pepsin from the stomach flows backward up into the esophagus often called heartburn. What Causes GERD? Overproduction of acid/pepsin Over relaxation of the Lower Esophageal Sphincter (LES); Complications; if not treated - severe chest pains, bleeding or a pre-malignant change in the lining of the esophagus called Barrett’s esophagus – can result in adenocarcinoma . 13

14. Drugs Used to Treat PUD and GERD cont… PUD: Definition A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin; Although the pathogenesis of PUD is not fully understood , several major causative factors are recognized: infection with gram-negative Helicobacter pylori, use of nonsteroidal anti-inflammatory drugs ( NSAIDs ), increased hydrochloric acid secretion , Stress related mucosal damage inadequate mucosal defense against gastric acid, and tumors (rare). 14

15. 15 Predisposing factors : Heridity & certain genetic factors Stress Smoking alcoholic intake bile reflux, excessive use of irritant drugs and foods decrease blood supply e.g. By thrombosis

16. 16 General measures : rest in bed (better in hospital) light small frequent meals , non irritant foods . salty foods should be avoided avoid smoking , coffee, tea or alcohol . avoid irritant drugs e.g. Aspirin; corticosteroids; Reserpine. avoid stress. surgical treatment is indicated in cases of : failure of Medical treatment (after 6 months ) or presence of Complications .

17. PUD cont… Treatment approaches include; eradicating the H. pylori infection, reducing secretion of gastric acid with the use of PPIs or H2-receptor antagonists, and/or providing agents that protect the gastric mucosa from damage , such as misoprostol and sucralfate. If patients are unable to tolerate the above therapies, neutralizing gastric acid with nonabsorbable antacids is an option. 17

18. Treatment of Heartburn, GERD and PUD Antacids H 2 Receptor Blockers Mucosal Protective Agents Proton Pump Inhibitors Anti-cholinergics Prostaglandin Analogs Anti-microbial Agents 18

19. Proton pump inhibitors (PPI) Omeprazole, Esomeprazole, Lansoprazole , Rabeprazole and pantoprazole MOA Prodrugs Absorption into the systemic circulation and then accumulation in parietal cell acidic secretory channel Covalent binding with sulfhydryl groups (-SH) of cysteine in the H + /K + -ATPase Irreversible inactivation of the pump molecule Acid secretion resumes only after new pump molecules are synthesized Have long duration of action (24-48h) despite short half life of the parent compound (0.5-2h)

20. 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 more than 90 %. they are also successfully used with antimicrobia l regimens to eradicate H. pylori. If an H 2 -receptor antagonist is also needed, it should be taken well after the PPI for best effect because the H 2 antagonists will reduce the activity of the proton pump, and PPIs require active pumps to be effective .

21. Pharmacokinetics The prodrugs are unstable in the presence of acid and therefore must be administered as Enteric-coated drugs Powdered drug combined with sodium bicarbonate (omeprazole) These drugs ideally should be given about 30 minutes before meals . Rate of absorption may be reduced by food. Once in the small bowel, they are rapidly absorbed, highly protein bound, and extensively metabolized

22. Therapeutic use stress ulcer treatment and prophylaxis, treating erosive esophagitis active duodenal ulcer , long-term treatment of pathologic hypersecretory conditions (e.g., Zollinger -Ellison syndrome, in which a gastrin-producing tumor causes hypersecretion of HCl ). Because not all proton pumps are inactivated with the first dose of medication , up to 3–4 days of daily medication are required before the full acid-inhibiting potential is reached. Similarly, after stopping the drug, it takes 3–4 days for full acid secretion to return .

23. Adverse Effects Most common: nausea, abdominal pain, diarrhea,, flatulence, and constipation. Subacute myopathy, headaches, and skin rashes have also been reported. Frequent, more severe Hypergastrinemia (risk of rebound hypersecretion upon discontinuation and gastrointestinal tumors)

24. Drug Interactions Because of the short half-lives of PPIs , clinically significant drug interactions are rare . Omeprazole may inhibit the metabolism of warfarin, diazepam, phenytoin, and cyclosporine. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline . Rabeprazole and pantoprazole have no significant drug interactions.

25. Therapeutic Uses to promote healing of gastric and duodenal ulcers and to treat gastroesophageal reflux disease (GERD) Treatment of hypersecretory conditions Treatment and prevention of recurrence of NSAID-associated gastric ulcers in patients who continue NSAID use ( Lansoprazole ). Reduce the risk of duodenal ulcer recurrence associated with H. pylori infections . In children, omeprazole is safe and effective for treatment of erosive esophagitis and GERD .

26. H 2 -Receptor antagonists Drugs : Cimetidine, Famotidine, Ranitidine, Nizatidine MOA Reversible antagonists of H 2 -histamine receptors on parietal cells  block histamine induced stimulation of acid secretion . Predominantly inhibit basal acid secretion  efficacious in suppressing nocturnal acid secretion

27. H 2 -blockers act by stopping acid secretion . Therefore, they may not relieve symptoms for at least 45 minutes. Compared to cimetidine, ranitidine is longer acting and is five- to ten-fold more potent . Ranitidine has minimal side effects and does not produce the anti-androgenic and prolactin-stimulating effects of cimetidine .

28. Pharmacokinetics Rapidly absorbed after oral administration, which may be enhanced by food or decreased by antacids. Only small %age of the drugs are protein-bound . Excretion: renal filtration and tubular secretion of the parent and metabolites, metabolism in liver (<10% to 35%). Dose adjustment may be required in patients with decreased creatinine clearance.

29. Adverse effects Generally well tolerated Include diarrhea , headache, drowsiness, fatigue, muscular pain, and constipation. Less common: confusion, delirium, hallucinations, slurred speech (with IV administration) Galactorrhea in women and gynecomastia , reduced sperm count, and impotence in men (with larger dose and/or prolonged use of cimetidine)

30. Drug interaction Cimetidine is an enzyme inhibitor and can increase the levels of a variety of drugs Ranitidine interferes only minimally with hepatic metabolism of other drugs. No significant drug interactions mediated by enzyme inhibition with Famotidine and nizatidine Antacids reduce absorption of all H2 blockers (a gap of 2 hrs should be allowed)

31. Therapeutic Uses. To promote healing of gastric and duodenal ulcers, To treat uncomplicated GERD, and To prevent the occurrence of stress ulcers.

32. Tolerance and Rebound with Acid-Suppressing Drugs Tolerance to the acid-suppressing effects of H 2 -receptor antagonists. Prolonged use, down-regulation of receptor occurs,  tolerance Does not occur with PPI , even with higher hypergastrinemia Rebound increases in gastric acidity can occur upon discontinuation of PPI as well as H 2 histamine receptor antagonists

33. Antacids The rationale lies in the assumption that buffering of H + in the stomach permits healing . NaHCO 3 Very water-soluble and rapidly absorbed from the stomach Alkali and sodium loads may pose a risk for patients with cardiac or renal failure   CaCO 3 Release of CO 2 from HCO 3 - - and CO 3 2- -containing antacids can cause belching, nausea, abdominal distension, and flatulence. Calcium may induce rebound acid secretion, necessitating more frequent administration .

34. Magnesium hydroxide May produce osmotic diarrhea Excessive absorption of Mg ++ in patients with renal failure may result in toxicity. Aluminum hydroxide Its use is associated with relaxation of gastric smooth muscle, producing delayed gastric emptying and constipation Serum phosphate levels also may become depressed because of phosphate binding within the gut.

35. By altering gastric and urinary pH , antacids may affect bioavailability of a number of drugs Al 3+ and Mg 2+ antacids chelate other drugs forming insoluble complexes that pass through the GI tract without absorption .

36. Misoprostol Which is an analogue of prostaglandin E 1 , Pharmacokinetics Absorbed rapidly after oral administration and is hydrolyzed to the active compound Metabolized by the liver and excreted mainly in the urine. Adverse effects Include crampy abdominal pain, dose-related diarrhea , and uterine contractions Therapeutic use Prevention of NSAID–induced ulceration, Treatment of PUD

37. Sucralfate Is an aluminum hydroxide–sulphated sucrose complex that is only minimally absorbed from the GIT. After exposure to gastric acid, the compound becomes negatively charged, creating a viscous adherent complex, which is believed to inhibit back-diffusion of H + . Also causes direct reduction in pepsin activity and stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth compounds have direct antimicrobial activity against H pylori

38. Use : frequently used for prophylaxis of stress-induced gastritis in patients in intensive care units. Adverse effects : Constipation , secondary hypophosphatemia (due to the aluminium). Binding to a number of other coadministered medications may result in a significant reduction in their bioavailability.

39. Antimicrobial agents Optimal therapy for patients with PUD (both duodenal and gastric ulcers) who are infected with H. pylori requires antimicrobial treatment. Eradication of H. pylori results in rapid healing of active peptic ulcers and low recurrence rates Successful eradication of H. pylori (80–90 %) is possible with various combinations of antimicrobial drugs . 39

40. Drugs against H. pylori Initial treatment (triple therapy for 7 to 10 days) Proton pump inhibitor (PPI), standard dose twice daily Rabeprazole, lansoprazole , omeprazole , pantoprazole , and esomeprazole in combination with 2 antimicrobials: Clarithromycin, and Amoxicillin (or metronidazole for penicillin allergic patients)

41. Alternative treatment and retreatment for patients who failed initial therapy (14 days) PPI (twice daily), and Metronidazole (4 times daily), and Tetracycline (4 times daily), and Bismuth subsalicylate (4 times daily) Bismuth salts do not neutralize stomach acid, but they do inhibit pepsin and increase the secretion of mucus . helps to form a barrier against the diffusion of acid in the ulcer.

42. Antiemetics

43. Nausea : inclination to vomit ( feeling in the throat or epigastric region alerting that vomiting is imminent) Vomitin g is the ejection/expulsion of gastric content through the mouth. Are protective reflexes that prevent further absorption from the GIT. Etiology GI, CV, Neurologic, metabolic, drug, pregnancy, irritant food/drug, noxious odours

44. Drugs Antihistamines Anticholinergics Canabinoids Centrally acting Dopamine antagonists 5-HT 3 Receptor Antagonists

45. Antihistamines Primarily useful for motion sickness and postoperative emesis They act on vestibular afferents and within the brainstem. Drugs: Cyclizine , hydroxyzine , promethazine, and diphenhydramine. Cyclizine has additional anticholinergic effect

46. Anticholinergics Drugs: scopolamine ( hyoscine ) In the prevention and treatment of motion sickness Use of antihistamine and anticholinergic drugs is limited by sedation, dizziness, confusion, dry mouth, cycloplegia , and urinary retention.

47. Canabinoids Dronabinol is  9 - tetrahydrocannabinol (THC), is the major psychoactive chemical in marijuana . The antiemetic site of action is unknown; appears to affect the central cerebral cortex axis Also has appetite stimulant effect From the marijuana plant , Cannabis sativa

48. Pharmacokinetics THC is a highly lipid-soluble  absorbed readily PO Extensive first-pass metabolism with limited systemic bioavailability (10% to 20%). Therapeutic Use Prophylactic agent in patients receiving cancer chemotherapy when other antiemetic medications are not effective. Appetite stimulate in patients with acquired immunodeficiency syndrome (AIDS) and anorexia.

49. Adverse Effects Palpitations, tachycardia, vasodilation, hypotension Euphoria , detachment, dizziness, anxiety, paranoid reactions and thinking abnormalities.

50. Centrally acting Dopamine antagonists Phenothiazines such as prochlorperazine , promethazine and chlorpromazine are among the most commonly used Principal MOA: dopamine D 2 -R antagonism at the CTZ . They also decrease vomiting caused by gastric irritants, suggesting that they inhibit stimulation of peripheral vagal and sympathetic afferents. Sedation frequently occur following their administration.

51. 5-HT 3 Receptor Antagonists During chemotherapy that induces vomiting, mucosal enterochromaffin cells in the GIT release serotonin, which stimulates 5-HT 3 Rs . This causes vagal afferent discharge, inducing vomiting. Drugs: Ondansetron , Granisetron , Dolasetron , tropisetron and Palonosetron (IV use only) Potent antagonists of 5-HT 3 Rs , on peripheral vagal nerve terminals and centrally in the CTZ .

52. 5-HT 3 Receptor Antagonists ( con’d ) Are the most widely used drugs for chemotherapy-induced emesis . Also used to prevent or treat post-operative nausea and vomiting Headache, dizziness, and constipation (most frequently reported adverse effect)

53. Metoclopramide MOA Dopamine receptor antagonism. Vagal and central 5-HT 3 -antagonism Sensitization of muscarinic receptors on smooth muscle Results in coordinated contractions that enhance transit. Increases lower esophageal sphincter tone Stimulates small intestinal contractions.

54. Pharmacokinetics Absorbed rapidly after oral ingestion, Metabolism in the liver and excreted principally in the urine, with a half-life of 4 to 6 hours. Therapeutic Use. Gastroesophageal reflux disease Ameliorate nausea and vomiting that accompany GI dysmotility syndromes .

55. Adverse Effects Extrapyramidal effects, parkinsonian -like symptoms, Like other dopamine antagonists , metoclopramide also can cause galactorrhea by blocking the inhibitory effect of dopamine on prolactin release,

56. Drugs that induce Emesis Includes - Ipecac syrup ( Cephaelis ipecacuanha ) Apomorphine (derivatives of morphin ) MA -- acts directly on the CTZ Induced emesis is the preferred means of emptying the stomach in awake patients who have ingested a toxic substance or have recently taken a drug overdose . APOMORPHINE It is given by subcutaneous/IM route in the dose of 6 mg and it produces vomiting within 15minutes .

57. Drugs Used in The Treatment of Constipation

58. Constipation Fluid content is the principal determinant of stool volume and consistency Net stool fluid content reflects a balance between luminal input (ingestion and secretion of water and electrolytes ) and output (absorption) along the length of the GI tract. Neurohumoral mechanisms, pathogens, and drugs can alter the balance  changes in either secretion or absorption of fluid by the intestinal epithelium. Decreased motility  excess fluid removal  constipation. When the capacity of the colon to absorb fluid is exceeded, diarrhea will occur

59. Constipation Normal stool frequency on a Western diet is at least 3 times a week Decreased frequency , difficulty in initiation or passage , passage of firm or small-volume feces , or a feeling of incomplete evacuation . Causes Lack of dietary fiber , drugs, hormonal disturbances, neurogenic disorders, and systemic illnesses. In most cases no specific cause is found.

60. Laxatives cause the evacuation of formed fecal material from the rectum while Cathartics cause evacuation of unformed , usually watery fecal material from the entire colon.

61. Laxatives 1. Stool-surfactant agents (Stool softeners) Docusate salts , glycerin suppository , Mineral oil Docusate salts Anionic surfactants that lower the surface tension of the stool  mixing of aqueous and fatty substances,  soft stool and easy defecation. Also stimulate intestinal fluid and electrolyte secretion Docusate sodium and docusate calcium

62. Stool softeners (cont’d) Mineral oil: mixture of aliphatic hydrocarbons, On oral administration, the oil penetrates and softens the stool , retarding water absorption from the stool . Unwanted effects : interference with absorption of fat-soluble substances (such as vitamins A,D,E,K),

63. 2. Osmotic laxatives Saline Laxatives / Nonabsorbable Salts Laxatives containing magnesium cations or phosphate anions : Magnesium sulfate , magnesium hydroxide (milk of magnesia), magnesium citrate, sodium phosphate. Osmotically mediated water retention  stimulates peristalsis. Other mechanisms Mg ++ containing laxatives  stimulate release of cholecystokinin ( major hormone responsible for gallbladder contraction )  intraluminal fluid and electrolyte accumulation and increased intestinal motility.

64. Magnesium- and phosphate-containing preparations: generally well tolerated. Use with caution or avoided in patients with renal insufficiency, cardiac disease, or pre-existing electrolyte abnormalities When taking these agents, it is very important that patients maintain adequate hydration

65. Nondigestible Sugars and Alcohols Sorbitol and mannitol  hydrolyzed to short-chain fatty acids  osmotically draw water into the lumen  stimulate colonic propulsive motility. In the treatment of constipation caused by opioids and vincristine, constipation in the elderly, and idiopathic chronic constipation . Abdominal discomfort and flatulence. Lactulose ( synthetic disaccharide of galactose and fructose that resists intestinal disaccharidase activity) Osmotic.. (cont’d)

66. Polyethylene Glycol- Electrolyte Solutions (Balanced PEG) Long-chain polyethylene glycols (PEGs): poorly absorbed, and retained in the lumen. Used widely for colonic cleansing for radiological, surgical, and endoscopic procedures To avoid net transfer of ions , preparations contain isotonic mixture of sodium sulfate , sodium bicarbonate, sodium chloride, and potassium chloride. Osmotic… (cont’d)

67. Is designed so that no significant intravascular fluid or electrolyte shifts occur. Therefore, they are safe for all patients. should be ingested rapidly (2–4 L over 2–4 hours) to promote bowel cleansing.

68. Have direct effects on enterocytes, enteric neurons, and GI smooth muscle . Mechanisms: activation of prostaglandin- cAMP Drugs: diphenylmethane derivatives, ricinoleic acid and anthraquinones 3. Stimulant (Irritant) Laxatives

69. Stimulant Laxatives (cont’d) Diphenylmethane Derivatives Phenolphthalein, Sodium picosulfate , Bisacodyl The diphenylmethanes can damage the mucosa and initiate an inflammatory response in the small bowel and colon Bisacodyl (tablet and suppository) for acute and chronic constipation . also used in conjunction with PEG solutions for colonic cleansing prior to colonoscopy.

70. induces a bowel movement within 6–10 hours when given orally and 30–60 minutes when taken rectally . It has minimal systemic absorption and appears to be safe for acute and long-term use. Phenolphthalein was removed from the market owing to concerns about possible cardiac toxicity .

71. Stimulant Laxatives (cont’d) Anthraquinone Laxatives Derivatives of plants aloe, cascara , and senna Chronic use leads to a characteristic brown pigmentation of the colon known as " melanosis coli.“ These laxatives are 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 .

72. Stimulant Laxatives (cont’d) Castor Oil Castor oil is derived from the bean of the castor plant, Ricinus communis  contains ricin (extremely toxic protein) and a triglyceride ricinoleic acid. The triglyceride is hydrolyzed into glycerol and ricinoleic acid  stimulates secretion of fluid and electrolytes and speed intestinal transit.

73. 4. Chloride Channel Activator Lubiprostone labeled for use in chronic constipation and irritable bowel syndrome (IBS) with predominant constipation acts by stimulating the type 2 chloride channel (ClC-2) in the small intestine. This increases chloride-rich fluid secretion into the intestine, which stimulates intestinal motility and shortens intestinal transit time

74. 5. Opioid Receptor Antagonists chronic therapy with opioids may cause constipation by decreasing intestinal motility These effects are mainly mediated through intestinal mu (  )-opioid receptors selective antagonists of  opioid receptor methylnaltrexone and alvimopan

75. do not readily cross the blood-brain barrier , they inhibit peripheral -opioid receptors without impacting analgesic effects within CNS Methylnaltrexone is approved for the treatment of opioid-induced constipation

76. 6. Serotonin 5-HT 4 -Receptor Agonists Stimulation of 5-HT 4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves stimulate second-order enteric neurons to promote the peristaltic reflex . enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide).

77. Serotonin 5-HT 4 -Rec…. Tegaserod serotonin5-HT 4 partial agonist that has high affinity for 5-HT 4 receptors for the treatment of patients with chronic constipation and IBS Removed from the market (serious CVS events) cisapride : Another partial 5-HT 4 agonist, also asociated with CVS events Prucalopride is a high-affinity 5-HT 4 agonist that is in clinical development .

78. ANTIDIARRHEAL AGENTS

79. Diarrhea " too rapid evacuation of too much fluid stools." Since stool weight is largely determined by stool water, most cases of diarrhea result from disorders of intestinal water and electrolyte transport. Increased osmotic load within the intestine Excessive secretion of electrolytes and water into the intestinal lumen Exudation of protein and fluid from the mucosa Altered intestinal motility resulting in rapid transit (and decreased fluid absorption). Severe diarrhea  dehydration and electrolyte imbalances

80. Oral rehydration therapy therefore is a cornerstone for patients with acute illnesses resulting in significant diarrhea . Pharmacotherapy of diarrhea should be reserved for patients with significant or persistent symptoms. 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.

81. 1. Bulk-Forming and Hydroscopic Agents Hydrophilic and poorly fermentable colloids or polymers such as carboxymethylcellulose and calcium polycarbophil Absorb water and increase stool bulk The mechanism is not clear , but they may work as gels to modify stool texture and viscosity and to produce a perception of decreased stool fluidity. Some of these agents also may bind bacterial toxins and bile salts.

82. Bulk-Forming.... Clays such as kaolin and other silicates such as hydrated magnesium aluminum silicate ( attapulgite ) bind water avidly and also may bind enterotoxins . Pectin is an indigestible carbohydrate derived from apples . Charcoal plays the same role as kaolin

83. 2. Bile Acid Sequestrants . Cholestyramine , colestipol , and colesevalam bind bile acids and some bacterial toxins. In the treatment of bile salt-induced diarrhea 3. Bismuth. Bismuth subsalicylate + HCl  Bismuth oxychloride ( unabsorbable ) + Salicylic acid Mechanism of action remains poorly understood. Has antisecretory , antiinflammatory , and antimicrobial effects . Nausea and abdominal cramps also are relieved by bismuth. Use for the prevention and treatment of traveler's diarrhea

84. Antimotility and Antisecretory Agents Opioids Effects on intestinal motility (  receptors), intestinal secretion (  receptors), or a bsorption (  and  receptors). Commonly used: diphenoxylate , difenoxin , and loperamide act principally via peripheral  -opioid receptors and are preferred over opioids that penetrate the CNS.

85. Loperamide Has  -receptor activity, is an orally active antidiarrheal agent. 40 to 50 times more potent than morphine as an antidiarrheal agent and penetrates the CNS poorly. It increases transit times , increases anal sphincter tone, has antisecretory activity (against cholera toxin and some forms of E. coli toxin) Loperamide : as adjunct in almost all forms of chronic diarrheal disease. It lacks significant abuse potential Overdosage can result in CNS depression (especially in children) and paralytic ileus.

86. Antimotility and Antisecretory Agents (Cont’d)  2 Adrenergic Receptor Agonists ( clonidine ) Inhibit secretion of fluid and electrolytes Increase intestinal transit time. Have a special role in diabetics chronic diarrhea , in whom autonomic neuropathy can lead to loss of noradrenergic innervation. Useful in diarrhea due to opiate withdrawal