Other Gastrointestinal Drugs 1

GI Drugs Antiemetics Antidiarrheals Drugs for irritable bowel syndrome Drugs for inflammatory bowel disease 2

Antiemetics Given to suppress nausea and vomiting Emetic response Complex reflex after activating vomiting center in medulla oblongata Several types of receptors involved in emetic response Serotonin, glucocorticoids, substance P, neurokinin1, dopamine, acetylcholine, and histamine Many antiemetics interact with one or more of the receptors 3

Antiemetics Serotonin receptor antagonists Granisetron, dolasetron, palonosetron Ondansetron (Zofran) First approved for chemotherapy-induced nausea and vomiting (CINV) Blocks type 3 serotonin receptors on afferent vagal nerve More effective when used with dexamethasone 4

Antiemetics Glucocorticoids Unknown mechanism of action (MOA) as antiemetic Methylprednisolone (Solu-Medrol) Dexamethasone (Decadron) Commonly used to suppress CINV, but this is not an FDA-approved application Effective alone and in combination with antiemetics 5

Antiemetics Substance P/neurokinin1 antagonists Aprepitant (Emend) Blocks neurokinin1-type receptors (for substance P) in the chemoreceptor trigger zone (CTZ) Prevents postoperative nausea/vomiting and CINV Prolonged duration of action (delayed CINV and acute) Adverse effects Drug interaction 6

Antiemetics Benzodiazepines Lorazepam (Ativan) Used in combination regimens to suppress CINV Three primary benefits Sedation Suppression of anticipatory emesis Production of anterograde amnesia 7

Antiemetics Dopamine antagonists Phenothiazines Block dopamine2 receptors in CTZ Surgery, cancer, chemotherapy, and toxins Side effects Extrapyramidal reactions Anticholinergic effects Hypotension and sedation 8

Antiemetics Butyrophenones Haloperidol (Haldol) and droperidol (Inapsine) Block dopamine2 receptors in CTZ Postoperative nausea/vomiting, chemotherapy emesis, radiation therapy, and toxins Side effects Similar to phenothiazines May cause prolonged QT and fatal dysrhythmias Electrocardiographic monitoring needed 9

Antiemetics Metoclopramide (Reglan) Blocks dopamine receptors in CTZ Postoperative nausea/vomiting, anticancer drug, opioids, toxins, radiation therapy Cannabinoids Dronabinol (Marinol) and nabilone (Cesamet) Related to marijuana CINV MOA with emesis unclear Potential for abuse and psychotomimetic effects 10

Management of Chemotherapy- Induced Nausea and Vomiting Three types of emesis Anticipatory Occurs before drugs are given Acute Onset within minutes to a few hours Delayed Onset 1 day or longer after drug received 11

Management of Chemotherapy-Induced Nausea and Vomiting Antiemetics are more effective in preventing CINV than suppressing CINV in progress Give before chemotherapy drugs Monotherapy and combination therapy may be needed 12

Drugs for Motion Sickness Scopolamine Muscarinic antagonist Side effects Dry mouth Blurred vision Drowsiness 13

Drugs for Motion Sickness Antihistamines Dimenhydrinate (Dramamine), meclizine (Antivert), cyclizine (Marezine) Considered anticholinergics—block receptors for acetylcholine and histamine Side effects Sedation (H1-receptor blocking) Dry mouth, blurred vision, urinary retention, constipation (muscarinic receptor blocking) 14

Diarrhea Characterized by stools of excessive volume and fluidity and increased frequency of defecation Symptom of GI disease Causes Infection, maldigestion, inflammation, functional disorders of the bowel Complications Dehydration and electrolyte depletion 15

Diarrhea Management Two major groups of antidiarrheals Diagnosis and treatment of underlying disease Replacement of lost water and salts Relief of cramping Reducing passage of unformed stools Two major groups of antidiarrheals Specific antidiarrheal drugs Nonspecific antidiarrheal drugs 16

Nonspecific Antidiarrheal Agents Opioids Most effective antidiarrheal agents Activate opioid receptors in GI tract Decrease intestinal motility Slow intestinal transit Allow more fluid to be absorbed Decrease secretion of fluid into small intestine and increase absorption of fluid and salt Diphenoxylate (Lomotil) and loperamide (Imodium) 17

Nonspecific Antidiarrheal Agents Opioids Diphenoxylate (Lomotil) Formulated with atropine to discourage abuse Opioid used only for diarrhea High doses can elicit typical morphine-like subjective responses Loperamide 18

Nonspecific Antidiarrheal Agents Difenoxin Paregoric Opium tincture Bismuth subsalicylate Bulk-forming agents Anticholinergic antispasmodics 19

Management of Infectious Diarrhea General considerations Variety of bacteria and protozoa can be responsible Infections are usually self-limited Many cases require no treatment Antibiotics should be used only when clearly indicated Traveler’s diarrhea 20

Irritable Bowel Syndrome IBS: most common disorder of GI tract 20% of Americans affected 3× higher incidence in women than in men Characterized by cramping abdominal pain (may be severe) that cannot be explained by structural or chemical abnormalities May occur with diarrhea, constipation, or both Considered IBS when symptoms have been present for 12 weeks over the past year 21

Irritable Bowel Syndrome Four groups of drugs historically used American College of Gastroenterology concluded that most of these agents do not have proof of clinical benefits Antispasmodics Bulk-forming agents Antidiarrheals Tricyclic antidepressants Two studies suggest that antibiotics or an acid suppressant may be effective for some patients 22

IBS-Specific Drugs Alosetron (Lotronex) Potentially dangerous drug; approved for women only GI toxicities can cause complicated constipation, leading to perforation and ischemic colitis Introduced in 2000, withdrawn in less than 10 months, and reintroduced in 2002 23

IBS-Specific Drugs Lubriprostone (Amitiza) Tegaserod (Zelnorm) Approved for constipation-predominant IBS in women age 18 years and older Tegaserod (Zelnorm) Short-term therapy of constipation-predominant IBS 24

Inflammatory Bowel Disease IBD: caused by exaggerated immune response against normal bowel flora Crohn’s disease Characterized by transmural inflammation Usually affects terminal ileum (can impact all parts of GI tract) Ulcerative colitis Inflammation of the mucosa and submucosa of the colon and rectum May cause rectal bleeding May require hospitalization 25

Drugs for IBD Not curative: may control disease process Aminosalicylates (sulfasalazine) Glucocorticoids (hydrocortisone) Immunosuppressants (azathioprine) Immunomodulators (infliximab) Antibiotics (metronidazole) 26

Prokinetic Agents Increase tone and motility of GI tract GERD, CINV, diabetic gastroparesis Metoclopramide (Reglan, Maxolon, Octamide) Blocks receptors for dopamine and serotonin in the CTZ Increases upper GI motility and suppresses emesis Cisapride (Propulsid) 27

Palifermin (Kepivance) First drug approved for decreasing oral mucositis (OM) Currently indicated only for patients with hematologic malignancies (can stimulate proliferation of malignant cells of nonhematologic origin) Synthetic form of human keratinocyte growth factor (KGF) Stimulates proliferation, differentiation, and migration of epithelial cells 28

Pancreatic Enzymes Deficiency of enzymes compromises digestion Pancreatin: hog or beef pancreas Pancrelipase: hog pancreas Preferred because enzyme activity is far greater than that of pancreatin Enteric-coated microspheres 29

Drugs Used to Dissolve Gallstones Chenodiol (chenodeoxycholic acid) Useful for radiolucent stones (not calcium) Increases production of bile acids Most successful in women with low cholesterol levels Ursodiol (ursodeoxycholic acid) Does not increase bile acids Reduces the cholesterol content of bile Gradual dissolution of stones 30

Anorectal Preparations Symptomatic relief of hemorrhoids and other anorectal disorders Local anesthetics Hydrocortisone Emollients Astringents Multiple formulations available 31