Advanced Pharmacology Gastrointestinal Pharmacology Handout Samples/Advanced... · Advanced Pharmacology Gastrointestinal Pharmacology Thomas W. Barkley, Jr., ... Osmotic Laxatives

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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


Drugs for Gastroesophageal RefluxDisease (GERD)

and Peptic Ulcer Disease (PUD)

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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


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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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


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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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


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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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


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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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


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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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)


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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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


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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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


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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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


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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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


Drugs for Constipation

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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


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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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


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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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)


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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Drugs for Diarrhea


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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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


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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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


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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Irritable Bowel Disease vs.Irritable Bowel Syndrome


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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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


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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Anatomic Distribution of IBD

http://www.hopkins-gi.org/pages/latin/templates/index.cfmpg=disease1&organ=6&disease=21&lang_id=1


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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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


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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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


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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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


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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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$$$


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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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


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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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


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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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 ?


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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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


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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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


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


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


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


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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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)


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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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


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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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


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)


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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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


Pharmacologic Therapy

http://www.nauseaandvomiting.co.uk/NAVRES001-4-opioid_files/image002.gif

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The End

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Advanced Pharmacology Gastrointestinal Pharmacology Handout Samples/Advanced... · Advanced Pharmacology Gastrointestinal Pharmacology Thomas W. Barkley, Jr., ... Osmotic Laxatives