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Unit 6 ©2014 Barkley & Associates
Advanced PharmacologyGastrointestinal Pharmacology
Thomas W. Barkley, Jr., PhD, ACNP‐BC, FAANPPresident, Barkley & Associates
www.NPcourses.comand
Professor of NursingDirector of Nurse Practitioner ProgramsCalifornia State University, Los Angeles
Robert Fellin, PharmD, BCPSFaculty, Barkley & Associates
Pharmacist, Cedars‐Sinai Medical CenterLos Angeles, CA
Unit 6 ©2014 Barkley & Associates
Drugs for Gastroesophageal RefluxDisease (GERD)
and Peptic Ulcer Disease (PUD)
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Unit 6 ©2014 Barkley & Associates
Gastroesophageal Reflux Disease (GERD) Movement of acid from the stomach into the esophagus Caused by a defective lower esophageal sphincter pressure
May lead to esophagitis, strictures, hemorrhage, Barrett’s esophagus
http://members.kaiserpermanente.org/kpweb/healthency.do?body=multimedia/hw142353/hw142353-sec.html&topic=Gastroesophageal+Reflux+Disease+%28GERD%29
Unit 6 ©2014 Barkley & Associates
GERD - Signs & Symptoms Typical: heartburn, regurgitation, acidic taste
in mouth Atypical: chronic cough, asthma-like
symptoms, sore throat, laryngitis/ hoarseness, non-cardiac chest pain
http://www.gicare.com/pated/ecdgs04.htm
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Unit 6 ©2014 Barkley & Associates
GERD - DiagnosisSymptoms heartburn, regurgitation Endoscopy visualization and grading of the esophageal mucosapH testing relationship between symptoms & abnormal acid exposure
http://www.gicare.com/pated/eieg0001.htmNORMAL GERD
Unit 6 ©2014 Barkley & Associates
Peptic Ulcer Disease (PUD) Imbalance between aggressive forces & defensive factors Most important to the development of PUD: bacterial GI
infection, NSAID ingestion and cigarette smoking May lead to hemorrhage/GI bleed
http://www.swedish.org/13735.cfm
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Unit 6 ©2014 Barkley & Associates
PUD - Signs & Symptoms Duodenal ulcer: epigastric pain (possibly worse at night), often occurs 1-3
hours following a meal and may be relieved by eating heartburn, belching, bloated feeling, nausea, anorexia
Gastric ulcer: epigastric pain often made worse with eating heartburn, belching, bloated feeling, nausea, anorexia
Unit 6 ©2014 Barkley & Associates
PUD - DiagnosisSymptoms epigastric pain
Endoscopy visualization of duodenal/gastric
mucosaH. Pylori testing serological urea breath test stool antigen test rapid urease test histology Culture PCR
http://www.gicare.com/pated/eieg0001.htmNORMAL GASTRIC ULCER
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Unit 6 ©2014 Barkley & Associates
Diagnostic Tests for H. Pylori InfectionSerology (ELISA) Used for diagnosis only
Urea breath test Diagnosis and confirmation of eradicationResults affected by acid suppressive agents (must be off for at least two weeks)
Stool antigen testing Diagnosis and confirmation of eradicationMonoclonal tests preferredResults affected by acid-suppressive agents
Rapid Urease test(requires endoscopy)
Diagnosis and confirmation of eradicationResults affected by acid suppressive agents (must be off for at least two weeks)
Biopsy with histology(requires endoscopy)
Diagnosis and confirmation of eradicationExcludes adenocarcinoma or MALT lymphoma
Culture(requires endoscopy)
Diagnosis of infectionEstablishment of antibiotic drug susceptibilities
Polymerase chain reaction(requires endoscopy)
Establishment of antibiotic susceptibilitiesIdentification of virulence factors or mutations associated with resistanceUsed mostly in the research setting
Unit 6 ©2014 Barkley & Associates
Nonpharmacologic Therapy - GERD Dietary avoid aggravating foods/beverages reduce fat intake and portion size remain upright following meals & avoid eating 3 hours
prior to bedtime Weight reduction Avoid tight fitting clothes
Reduce/discontinue nicotine use
Elevate the head of the bed (8-10”)
Avoid medications that affect LES
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Unit 6 ©2014 Barkley & Associates
AntacidsIndications: Short-term/intermittent relief of heartburn
Agents: Various OTC agents available: aluminum hydroxide (AlternaGEL, Amphojel), calcium carbonate (Tums), magnesium hydroxide (Milk of Magnesia), magnesium hydroxide and aluminum hydroxide (Maalox), magnesium hydroxide and aluminum hydroxide with simethicone (Mylanta, Maalox Plus), magaldrate (Riopan), sodium bicarbonate (Alka-Seltzer)
MOA: neutralizes acid and raises intragastric pH
Adverse Effects: constipation, diarrhea, acid-base disturbances
Comments: Avoid aluminum & magnesium containing products in severe renal impairmentPrevents absorption of other drugsNOT appropriate for healing of established esophageal or gastric erosionsRequires frequent dosingVery rapid acting
Unit 6 ©2014 Barkley & Associates
Antacid + Alginic AcidIndications: Short-term/intermittent relief of heartburn
Agents: Various OTC agents available: Gaviscon
MOA: forms a highly viscous solution that floats on the surface of the gastric contents to act as a barrier to reflux
Adverse Effects: nausea, constipation, diarrhea
Comments: NOT appropriate for healing of established esophageal erosionsNOT a potent neutralizing agentDoes NOT enhance LES pressureRequires frequent dosingPrevents absorption of other drugsVery rapid acting
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Unit 6 ©2014 Barkley & Associates
Histamine2-Receptor AntagonistsIndications: Heartburn, PUD, GERD, stress ulcer prophylaxis
Agents: famotidine (Pepcid), ranitidine (Zantac), cimetidine (Tagamet), nizatidine (Axid)
MOA: Inhibition of gastric acid secretion
Adverse Effects: Headache, dizziness, fatigue, somnolence and confusion; gynecomastia (cimetidine), thrombocytopenia
Comments: Less effective than PPI therapy in healing erosive esophagitisSeveral drug-drug interactions (cimetidine)Renal dysfunction requires dose adjustment (all)Available as OTC (all)May affect absorption of other drugs (all)
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Proton-Pump InhibitorsIndications: PUD, GERD, Zollinger-Ellison syndrome
Agents: omeprazole, (Prilosec) lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), esomeprazole (Nexium), dexlansoprazole (Dexilant)
MOA: Inhibition of gastric acid secretion
Adverse Effects: Headache, diarrhea, constipation, abdominal pain, nausea
Comments: No adjustment needed for renal dysfunctionAdminister 30 minutes prior to mealSlow onset; long duration of actionPotential increased risk of Clostridium difficileSeveral drug interactionsSuperior to H2 receptor antagonists
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Unit 6 ©2014 Barkley & Associates
Mucosal ProtectantsIndications: PUD, stress ulcer prophylaxis
Agents: sucralfate (Carafate)
MOA: forms a viscous adhesive that promotes ulcer healing
Adverse Effects: constipation, nausea, dry mouth, metallic taste, aluminum toxicity
Comments: Inhibits absorption of drugsDoes not effectively heal ulcers; relieves symptoms onlyRequires QID dosingAccumulates in renal insufficiencyNot for acute symptoms
Unit 6 ©2014 Barkley & Associates
ProstaglandinsIndications: Prophylaxis for NSAID induced gastric ulcer
Agents: misoprostol (Cytotec)
MOA: Moderately inhibits acid secretion and enhances production of mucus & bicarbonate (mucosal defense)
Adverse Effects: Diarrhea, abdominal cramping, nausea, flatulence, headache
Comments: Abortifacient; confirm adequate contraception in women of childbearing ageEffectively prevents gastric ulcers in patients receiving NSAID’sRequires QID dosing
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Unit 6 ©2014 Barkley & Associates
Prokinetic AgentsIndications: Adjunct therapy for GERD
Agents: metoclopramide (Reglan)
MOA: Increases LES pressure and accelerates gastric emptying
Adverse Effects: Dizziness, fatigue, somnolence, drowsiness, Tardive dyskinesia, hyperprolactinemia, cardiac dysrhythmia, neuroleptic malignant syndrome
Comments: Provides symptomatic improvement for some patients with GERDAdjust dose in renal impairmentMultiple drug interactions
Unit 6 ©2014 Barkley & Associates
Drugs for H. Pylori EradicationPatients who are not allergic to penicillin and have not previously received a macrolide
Standard dose PPI twice daily (or esomeprazole 40 mg once daily) + clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice dailyx 10-14 days
Patients who are allergic to penicillin, and who have not previously received a macrolide or metronidazole or are unable to tolerate bismuth quadruple therapy
Standard dose PPI twice daily +clarithromycin 500 mg twice daily +metronidazole 500 mg twice dailyx 10-14 days
Patients who are allergic to penicillin or failed one course (above) of H. pyloritreatment
Standard dose PPI twice daily + bismuth subsalicylate 525 mg QID+ metronidazole 250 mg QID +tetracycline 500 mg QID x 10-14 days
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Unit 6 ©2014 Barkley & Associates
Stress Ulcer Prophylaxis Stress related injury: superficial diffuse upper GI ulceration Stress ulcer: deeper mucosal ulceration; may lead to
bleeding and hemodynamic compromise Contributing factors: Hypoperfusion of the GI tract Alterations in gastric motility Loss of defense mechanisms: mucosal/bicarbonate layer,
prostaglandins
Unit 6 ©2014 Barkley & Associates
Stress Ulcer Prophylaxis Pharmacologic Strategies: antacids (?) sucralfate (?) histamine2-receptor antagonists proton-pump inhibitors
NOT routinely recommended in non-intensive care unit settings
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Unit 6 ©2014 Barkley & Associates
Upper Gastrointestinal Bleeding (UGIB):Nonvariceal Bleeding Primarily induced by NSAID use
Most frequent symptom is hematemesis or “coffee-ground”emesis
Management Volume resuscitation and hemodynamic stabilization Endoscopic intervention IV proton-pump inhibitors continuous infusion vs. IVPB
H2RA or somatostatin/octreotide NOT recommended
Unit 6 ©2014 Barkley & Associates
Drugs for Constipation
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Unit 6 ©2014 Barkley & Associates
Constipation: Major Causes Lack of exercise Insufficient fluid intake Medications that decrease motility: Opioids Anticholinergics Antihistamines
Foods: Alcoholic beverages Refined white flour products Dairy products Chocolate
Unit 6 ©2014 Barkley & Associates
Bulk-Forming LaxativesAgents: methylcellulose (Citrucel), psyllium (Metamucil),
polycarbophil (FiberCon)
MOA: Indigestible colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis
Adverse Effects: Increased bloating, flatus, abdominal fullness
Comments: Preferred agents for treatment and preventionSlow onset of action, not used for rapid reliefMaintain adequate hydrationEsophageal/GI obstruction if taken with insufficient fluid
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Unit 6 ©2014 Barkley & Associates
Osmotic LaxativesAgents: magnesium hydroxide (Milk of Magnesia, MOM), sorbitol,
lactulose, magnesium citrate, sodium biphosphate (Fleet Phospho-Soda), polyethylene glycol (PEG, MiraLAX)
MOA: Soluble but non-absorbable compounds that draw water into fecal mass, create watery stool
Adverse Effects: Severe flatus, diarrhea, abdominal cramping, electrolytedisturbances
Comments: Uses: colonic cleansing before GI proceduressorbitol, lactulose: prevent/treat chronic constipationProduce prompt BM; within 1-3 hoursMaintain adequate hydration with regular useMOM should not be used for prolonged periods in patients with renal insufficiency due to the risk of hypermagnesemia
Unit 6 ©2014 Barkley & Associates
Stimulant LaxativesAgents: senna (Ex-Lax, Senokot), bisacodyl (Correctol, Dulcolax)
MOA: Direct stimulation of the enteric nervous system; irritate bowel mucosa
Adverse Effects: Abdominal cramping, nausea, fainting, diarrhea, fluid and electrolyte loss
Comments: Work rapidlyUses: acute and chronic constipationMay be required on a long-term basis, especially in patients who are neurologically impairedSafe for acute and long-term useAdjunct to chronic opioid therapy ?
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Unit 6 ©2014 Barkley & Associates
Stool Surfactant Agents (Softeners)Agents: docusate (Colace), glycerin, mineral oil
MOA: Cause water and lipids to penetrate/be absorbed into stools; lubricates the stool
Adverse Effects: Abdominal cramping, diarrhea, nausea, nutritional deficiencies (mineral oil), aspiration pneumonia (mineral oil)
Comments: Prevent constipation and minimize strainingIneffective at treating constipationMineral oil: long-term use can impair absorption of fat-soluble vitamins (A, D, E, K)Docusate: most frequently used laxative to prevent constipation (given when iron and calcium supplementation prescribed)
Unit 6 ©2014 Barkley & Associates
Opioid Receptor AntagonistsAgents: alvimopan (Entereg), methylnaltrexone (Relistor)
MOA: Opioid receptor antagonists; inhibit peripheral opioid receptors without impacting analgesic effects in CNS
Adverse Effects: Diaphoresis, abdominal pain, flatulence, nausea, dizziness,gastrointestinal perforation
Comments: Methylnaltrexone: treatment of opioid-induced constipation in patients receiving palliative care for advanced illness who have had inadequate response to other agents; SQ only
Alvimopan: shorten the period of postoperative ileus in hospitalized patients who have undergone small/large bowel resectionShort-term use only (not to exceed 15 doses)Do not use in ESRD or liver impairmentREMS program due to cardiovascular toxicity (MI)
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Unit 6 ©2014 Barkley & Associates
Drugs for Diarrhea
Unit 6 ©2014 Barkley & Associates
Diarrhea: Pathophysiology Review When the large intestine does not reabsorb enough water from fecal watery stools
Causes: Medications, infections, viruses and substances (e.g., lactulose)
Antibiotics kills the normal flora of the gut diarrhea (overgrowth of pathologic organisms)
Primary goal of treatment: Assess and treat the underlying cause of diarrhea
Should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition
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Unit 6 ©2014 Barkley & Associates
Opioid AgonistsAgents: diphenoxylate with atropine (Lomotil), difenoxin with atropine
(Motofen), loperamide (Imodium), opium*
MOA: Diminish propulsive peristalsis; delays passage of fecal mass; allows increased absorption of water
Adverse Effects:
Drowsiness, light-headedness, nausea, dizziness, dry mouth (from atropine), constipation, paralytic ileus w/ toxic megacolon
Comments: Loperamide: no analgesic properties or potential for addictionDiphenoxylate: higher doses have central nervous system effects; prolonged use can lead to opioid dependence; combined with small amounts of atropine to discourage overdoseDiphenoxylate: Schedule V controlled substanceNot been found to be safe/effective; product labeling not approved by the FDA
Unit 6 ©2014 Barkley & Associates
Bile Salt-Binding ResinsAgents: cholestyramine, colestipol, colesevelam
MOA: Decrease diarrhea caused by excess fecal bile acids;bulking agents
Adverse Effects: Bloating, flatulence, constipation, fecal impaction, fat malabsorption
Comments: Disease of the terminal ileum (CD) or surgical resection leads to malabsorption of bile salts, causing colonic secretory diarrheaDo not administer within 2 hours of other drugsColesevelam does not appear to have significant effects on absorption of other drugs
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Unit 6 ©2014 Barkley & Associates
Bismuth CompoundsAgents: bismuth subsalicylate (Pepto-Bismol, Kaopectate)
MOA: Exact mechanism has not been determined; stimulating absorption of fluid and electrolytes across the intestinal wall; inhibiting synthesis of a prostaglandin responsible for intestinal inflammation and hypermotility
Adverse Effects: Blackening of the stool, darkening of the tongue, nausea
Comments: Uses: dyspepsia, acute diarrhea, prevention of traveler's diarrheaUsed for short periods onlyAvoid in patients with renal insufficiency
Unit 6 ©2014 Barkley & Associates
Octreotide (Sandostatin) Indication: secretory diarrhea secondary to GI
neuroendocrine tumors MOA: reduces intestinal fluid secretion; slows
gastrointestinal motility Dose: 100-150 mcg SQ q8h Adverse effects: nausea, abdominal pain, flatulence,
diarrhea, gallstones, hypothyroidism, hyper/hypoglycemia, dizziness, headache
Available only as SQ Optimal dosing and timing not yet defined for non-secretory
diarrhea
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Unit 6 ©2014 Barkley & Associates
Irritable Bowel Disease vs.Irritable Bowel Syndrome
Unit 6 ©2014 Barkley & Associates
Inflammatory Bowel Disease (IBD)
Two major disorders of IBD:
Ulcerative colitis (UC)
Crohn’s disease (CD)
At least 1 million Americans have IBD
Both men and women are affected equally
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Unit 6 ©2014 Barkley & Associates
Etiology
Infectious factors theory
Microflora of GI tract may activate inflammatory process
Immunologic mechanisms
Abnormal regulation of the immune response
Genetic factors
1st degree relatives have 13-fold increase in risk
Psychological factors
Mental health changes correlate with remissions & exacerbations
Diet and smoking
Diet habits do not appear to play a role in the development if IBD
Smoking plays an important but contrasting role in UC and CD
Unit 6 ©2014 Barkley & Associates
Clinical Features of IBDCROHN’S DISEASE ULCERATIVE COLITIS
Location Mouth to anus Colon and rectum
Distribution Segmental, focal, transmural, rigid, thick, edematous, fibrotic
Continuous, diffuse, mucosal
Gross Rectal Bleeding Infrequent Common
Fever/Malaise Common Infrequent
Abdominal mass Common Absent
Abdominal pain Common Infrequent
Abdominal tenderness Common May be present
Crypt abscesses Infrequent Common
Fistulas Very common Infrequent
Strictures/Granulomas Common Infrequent
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Unit 6 ©2014 Barkley & Associates
Anatomic Distribution of IBD
http://www.hopkins-gi.org/pages/latin/templates/index.cfmpg=disease1&organ=6&disease=21&lang_id=1
Unit 6 ©2014 Barkley & Associates
Pathologic Features of IBD
http://www.hopkins-gi.org/pages/latin/templates/index.cfm?pg=disease1&organ=6&disease=21&lang_id=1
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Unit 6 ©2014 Barkley & Associates
Clinical Manifestations
FeverAbdominal pain
DiarrheaRectal bleeding
Weight loss
Crohn’s Disease
Ulcerative colitis
May be anywhere from mouth to anusUlcerations extend to submucosa or deeperPatchy inflammationFistulas/perforation/strictures
Primarily confined to rectum and colonCrypt abscessesSuperficial ulcerationsContinuous inflammationToxic megacolon
Unit 6 ©2014 Barkley & Associates
Diagnosis
Crohn’s Disease:
No one conclusive diagnostic test
Patient's medical history & physical exam
Certain blood and stool tests are performed
Visualization of the small intestine, colon and the lining of the rectum and lower bowel
Ulcerative colitis:
Symptoms
Certain blood and stool tests are performed to rule out infection
Visual examination of the lining of the rectum and lower colon or the entire colon
Small, painless biopsies
Barium enema x-ray of the colon
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Unit 6 ©2014 Barkley & Associates
Nonpharmacologic Therapy Nutritional Support Eliminate foods that exacerbate symptoms Maintain adequate hydration Vitamin and mineral supplementation Fish oil supplementation (?) Parenteral nutrition/complete bowel rest
Surgery Curative for UC not for CD Resection of segments of the affected intestine Correction of complications (fistulas) or drainage of
abscesses
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AminosalicylatesIndications: Induction and maintenance of remission
Agents: sulfasalazine (Azulfadine), mesalamine (Asacol, Pentasa), balsalazide (Colazal), olsalazine (Dipentum)
MOA: Topical anti-inflammatory effect
AdverseEffects:
Nausea, vomiting, headache, hypersensitivity (sulfasalazine)
Comments: Adjust dose in renal impairmentAdministration: oral, rectal (enema, suppository)
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Unit 6 ©2014 Barkley & Associates
CorticosteroidsIndications: Induction of remission
Agents: prednisone (Deltasone), methylprednisolone (Solu-Medrol), budesonide (Entocort), hydrocortisone
MOA: Systemic anti-inflammatory
Adverse
Effects:
Nausea, vomiting, weight gain, water retention, osteoporosis, hyperglycemia
Comments: Administration: oral, IV and rectal (enema, suppository)Work quickly to suppress acute flaresNO role for maintenance therapyTaper dose after remission is achieved
Unit 6 ©2014 Barkley & Associates
ImmunomodulatorsIndications: Maintenance of remission; acute flares unresponsive to
steroids
Agents: 6-mercaptopurine (Purinethol), azathioprine (Imuran), cyclosporine (Neoral), methotrexate (Trexall)
MOA: Inhibits immune response
Adverse
Effects:
Nausea, pancreatitis, bone marrow suppression, hepatotoxicity
Comments: “Steroid-sparing” agentsAdministration: oral, IVSeveral drug interactionsMonitor drug levels (cyclosporine)
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Unit 6 ©2014 Barkley & Associates
ANTI-TUMOR NECROSIS FACTOR AGENTSIndications: Induction and maintenance of remission in patients with
Crohn’s disease
Agents: infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia)
MOA: Neutralizes tumor necrosis factor (TNF) and alters immune response
Adverse
Effects:
Fever, chills, pruritus, urticaria, chest pain, hypotension, infection, hypersensitivity
Comments: Administration: IV infusion, SQPPD prior to therapy to rule out TB$$$
Unit 6 ©2014 Barkley & Associates
AntibioticsIndications: Crohn’s disease (generally second-line)
Agents: metronidazole (Flagyl), ciprofloxacin (Cipro)
MOA: Bacterial flora may contribute to pathogenesis of inflammatory bowel disease
Adverse Effects: Diarrhea, photosensitivity, disulfiram reaction (metronidazole)
Comments: Many drug-drug interactionsSeveral drug-food interactionsNo benefit for UC patientsResistance (?)
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Unit 6 ©2014 Barkley & Associates
NicotineIndications: Ulcerative colitis (generally second-line)
Agents: nicotine transdermal patch
MOA: Unknown; affect smooth muscle in colon (?)
Adverse Effects: Skin irritation (erythema, pruritus, edema, rash), tachycardia, HA, insomnia, nervousness
Comments: May be beneficial for the treatment of active UC, but ineffective as maintenance therapy
No role in CD patients; worsens CD
More controlled trials are needed
Unit 6 ©2014 Barkley & Associates
Adjunct TherapySymptomatic management of IBD is important to the patient’s quality of life
Antidiarrheals
use with caution in severe disease; may precipitate toxic megacolon
loperamide (Imodium)/diphenoxylate-atropine (Lomotil)
Antispasmodics
dicyclomine (Bentyl)
propantheline (Pro-Banthine)
hyoscyamine (Levsin)
Cholestyramine (Questran)
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Unit 6 ©2014 Barkley & Associates
Irritable Bowel Syndrome (IBS) One of the most common GI disorders encountered in clinical
practice Affects as many as 20% of adults worldwide Although benign, IBS is chronic and recurring in nature Exacerbated by psychological stress More common in women
Unit 6 ©2014 Barkley & Associates
Classification & Treatment of IBS Constipation predominant disease (IBS-C)
Dietary modification
Laxatives (MOM, MiraLAX, bisacodyl, lactulose)
Diarrhea predominant disease (IBS-D)
Avoidance of certain food products (caffeine, alcohol), rule out lactose intolerance
Antidiarrheals (loperamide, cholestyramine)
Mixed pattern disease (IBS-M)
Abdominal pain
Antispasmodics (dicyclomine, hyoscyamine)
Antidepressants (?)
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Unit 6 ©2014 Barkley & Associates
Lubiprostone (Amitiza) Indication: IBS-C, chronic idiopathic constipation
MOA: enhances intestinal fluid secretion and acts as a laxative
Dose: 8 mcg PO BID
Adverse effects: abdominal distension, HA, abdominal pain, diarrhea, flatulence, nausea
Approved for use in women; efficacy in men not confirmed/established
Reserved for patients who have failed other therapy
Efficacy in treatment of opioid-induced constipation ?
Unit 6 ©2014 Barkley & Associates
Linaclotide (Linzess) Indication: IBS-C; chronic idiopathic constipation
MOA: stimulates the secretion of chloride and bicarbonate into the intestinal lumen, causing an increase in intestinal fluid and faster transit time
Dose: 290 mcg PO Daily
Adverse effects: abdominal distension, abdominal pain, diarrhea, flatulence, diarrhea
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Unit 6 ©2014 Barkley & Associates
Alosetron (Lotronex) Indication: IBS-D
MOA: serotonin receptor antagonist; blunts/reduces the hyperactivity of the GI tract
Dose: 0.5 mg PO BID
Adverse effects: constipation; nausea and GI discomfort, abdominal pain, ischemic colitis
June 2002, US FDA approved a supplemental NDA: allows the marketing of alosetron with restrictions
Caution: only for women with severe diarrhea-predominant IBS failing more conventional therapy
REMS program
Unit 6 ©2014 Barkley & Associates
AntidepressantsIndications: Improve abdominal pain and global symptoms of IBS
Agents: amitriptyline (Elavil), desipramine (Norpramin), citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft)
MOA: Analgesic properties (all), slow GI transit time (TCA’s); increase GI transit time (SSRI’s)
Adverse Effects: Anticholinergic effects, sedation, insomnia, orthostasis, HA, sexual dysfunction, somnolence
Comments: SSRI use is more controversial; lacks evidenceBest used when pain is the predominant symptomOnset of action: 4 weeks
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Unit 6 ©2014 Barkley & Associates
AntispasmodicsIndications: Improve abdominal pain or bloating of IBS
Agents: dicyclomine (Bentyl), hyoscyamine (Levsin)
MOA: Smooth muscle relaxation
Adverse Effects: Dry mouth, flushing, nausea, vomiting, tachycardia, urinary retention, dizziness, sedation, blurred vision
Comments: Can be used for IBS-C, IBS-D, IBS-MExperts advocate use on a “prn” basis rather than continuous dosing
Unit 6 ©2014 Barkley & Associates
Drugs for Nausea/Vomiting
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Pathophysiology Vomiting is triggered by impulses to the vomiting center, a
nucleus of cells in the medulla
http://www.rxfactstat.com/Diseases/nausea.htm
Unit 6 ©2014 Barkley & Associates
Pathophysiology Impulses are received from sensory centers, such as the
chemoreceptor trigger zone (CTZ), cerebral cortex and visceral afferents from the pharynx and GI tract
http://www.nurseminerva.co.uk/images/nausea1.gif
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Pathophysiology When excited, afferent impulses are integrated by the vomiting
center, resulting in efferent impulses to the salivation center, respiratory center and the pharyngeal, GI and abdominal muscles, leading to vomiting
http://www.vivo.colostate.edu/hbooks/pathphys/digestion/stomach/vomiting.html
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Pathophysiology
http://www.nauseaandvomiting.co.uk/NAVRES001-4-opioid.htm
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Etiology Gastrointestinal Mechanisms gastroparesis
Cardiovascular Diseases acute MI
Metabolic Disorders renal disease
Neurologic Processes migraine HA
Psychogenic Causes anticipatory
Therapy Induced Causes cytotoxic chemotherapy
Drug Withdrawal opiates
Miscellaneous pregnancy operative procedures
Unit 6 ©2014 Barkley & Associates
Antihistamine-Anticholinergic AgentsIndications: Simple N/V; N/V due to motion sickness, in
combination for more complex N/V
Agents: Dimenhydrinate (Dramamine), diphenhydramine (Benadryl), hydroxyzine (Atarax), meclizine (Bonine), scopolamine (Transderm Scop)
MOA: Interrupts various visceral afferent pathways that stimulate nausea and vomiting
Adverse Effects: Drowsiness, confusion, blurred vision, dry mouth, urinary retention, tachycardia
Comments: Higher doses/more frequent administration increases the risk of anticholinergic adverse effects
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Unit 6 ©2014 Barkley & Associates
PhenothiazinesIndications: Simple nausea and vomiting; mildly emetogenic
doses of chemotherapy; in combination for more complex N/V
Agents: Chlorpromazine (Thorazine), perphenazine (Trilafon), prochlorperazine (Compazine), promethazine (Phenergan)
MOA: Block dopamine receptors, most likely in the CTZ
Adverse Effects: Extrapyramidal reactions, marrow aplasia, excessive sedation, cardiac arrhythmias
Comments: Excess sedation (especially in the elderly)
Unit 6 ©2014 Barkley & Associates
ButyrophenonesIndications: Post-operative nausea and vomiting (PONV),
adjunct for chemotherapy induced nausea/vomiting (CINV)
Agents: Droperidol (Inapsine)
MOA: Blocks dopaminergic stimulation of the CTZ
Adverse Effects: Sedation, dystonic reactions, cardiac arrhythmias
Comments: Higher doses (> 2.5 mg) may increase the risk of cardiac arrhythmias
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Unit 6 ©2014 Barkley & Associates
CorticosteroidsIndications: PONV, CINV
Agents: Dexamethasone (Decadron), methylprednisolone (Solu-Medrol)
MOA: Unknown; inhibition of prostaglandin synthesis may play a role
Adverse Effects: Mood changes (anxiety to euphoria), HA, metallic taste, abdominal discomfort, hyperglycemia, itchy throat
Comments: NOT indicated for simple nausea and vomiting
Monitor blood glucose in DM patients
Unit 6 ©2014 Barkley & Associates
Metoclopramide (Reglan)Indications: PONV, CINV, delayed CINV
MOA: Blocks dopaminergic receptors in the CTZ; stimulates cholinergic activity in the gut increasing gut motility; blocks serotonin receptors in the intestines
Adverse Effects: Extrapyramidal effects, dystonic reactions, restlessness, drowsiness, fatigue, nausea, diarrhea, urinary retention, tachycardia, arrhythmia
Comments: Give with IV diphenhydramine to avoid EPS (delayed CINV)
Adjust dose in renal dysfunction
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Unit 6 ©2014 Barkley & Associates
Selective Serotonin AntagonistsIndications: PONV, CINV, delayed CINV
Agents: Ondansetron (Zofran), dolasetron (Anzemet), granisetron (Kytril), palonosetron (Aloxi)
MOA: Blocks serotonin receptors in the medulla, as well as those located along the vagal afferent nerves in the GI tract
Adverse Effects: Generally well tolerated; diarrhea, HA, fever, constipation, dizziness, drowsiness, arrhythmias
Comments: ALL agents have similar efficacyMay not be effective for controlling delayed emesis as monotherapy
Unit 6 ©2014 Barkley & Associates
CannabinoidsIndications: Nausea and vomiting associated with cancer
chemotherapy
Agents: Dronabinol (Marinol), nabilone (Cesamet)
MOA: Inhibition of prostaglandins or blocking adrenergic activity
Adverse Effects: Mood changes, anxiety, hallucinations, memory loss, fear, confusion, euphoria, hunger, time distortion, vertigo, sedation
Comments: Dependence (?)
Reserved for patients who fail to respond adequately to other antiemetic agents
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BenzodiazepinesIndications: Anticipatory nausea and vomiting; rescue nausea
and vomiting
Agents: Lorazepam (Ativan), diazepam (Valium)
MOA: Causes antegrade amnesia and decreases associated anxiety that may contribute to vomiting
Adverse Effects: Sedation, hypnosis, anxiolytic, muscle relaxation, disorientation, hallucinations, urinary incontinence
Comments: Increased fall risk due to over sedation (especially in the elderly)
Unit 6 ©2014 Barkley & Associates
Neurokinin-1 (NK-1) Receptor Antagonist
Examples: aprepitant (Emend) Indications: delayed nausea and vomiting secondary to
chemotherapy MOA: antagonizes neurokinin (which mediates emesis) Adverse effects: asthenia, dizziness, hiccups, fatigue,
elevated LFT’s and BUN Drug interactions: warfarin, oral contraceptives NOT recommended for long-term use in nausea and
vomiting
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Unit 6 ©2014 Barkley & Associates
Trimethobenzamide (Tigan) Indications: simple N/V; PONV MOA: inhibits stimulation of the CTZ Adverse effects: well tolerated; hypotension, somnolence,
anticholinergic effects, EPS Alternative for patients with allergies or intolerances to other
agents Offers no advantage over other agents; should be reserved
for patients unresponsive to primary agents Available as IM/PO
Unit 6 ©2014 Barkley & Associates
Pharmacologic Therapy
http://www.nauseaandvomiting.co.uk/NAVRES001-4-opioid_files/image002.gif
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Unit 6 ©2014 Barkley & Associates
The End