Chapter 16 Cholinesterase Inhibitors

Transcript Chapter 16 Cholinesterase Inhibitors

Chapter 80 Other Gastrointestinal Drugs

GI Drugs

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, neurokinin 1 , dopamine, acetylcholine, and histamine Many antiemetics interact with one or more of the receptors Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Antiemetics

 Substance P/neurokinin 1  antagonists Aprepitant (Emend) • Blocks neurokinin 1 -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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Antiemetics

 Benzodiazepines   Lorazepam (Ativan) Used in combination regimens to suppress CINV  Three primary benefits • Sedation • • Suppression of anticipatory emesis Production of anterograde amnesia Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Antiemetics

 Dopamine antagonists  Phenothiazines • Block dopamine 2 • • Surgery, cancer, chemotherapy, and toxins Side effects receptors in CTZ  Extrapyramidal reactions  Anticholinergic effects  Hypotension and sedation Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Antiemetics

 Butyrophenones  Haloperidol (Haldol) and droperidol (Inapsine) • Block dopamine 2 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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Drugs for Motion Sickness

 Antihistamines    Dimenhydrinate (Dramamine), meclizine (Antivert), cyclizine (Marezine) Considered anticholinergics —block receptors for acetylcholine and histamine Side effects • Sedation (H 1 -receptor blocking) • Dry mouth, blurred vision, urinary retention, constipation (muscarinic receptor blocking) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Diarrhea

  Management   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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Nonspecific Antidiarrheal Agents

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

IBS-Specific Drugs

  Lubriprostone (Amitiza)  Approved for constipation-predominant IBS in women age 18 years and older Tegaserod (Zelnorm)  Short-term therapy of constipation-predominant IBS Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Drugs for IBD

 Not curative: may control disease process   Aminosalicylates (sulfasalazine) Glucocorticoids (hydrocortisone)    Immunosuppressants (azathioprine) Immunomodulators (infliximab) Antibiotics (metronidazole) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Anorectal Preparations

  Symptomatic relief of hemorrhoids and other anorectal disorders  Local anesthetics    Hydrocortisone Emollients Astringents Multiple formulations available Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.