Contents
Cover
Title Page
Copyright
List of contributors
Preface
PART I: UPPER GI TRACT
Chapter 1: Prokinetic agents and antiemetics
Prokinetics
Antiemetic agents
Recommended reading
Chapter 2: Proton pump inhibitors
Introduction
Mechanism of action, pharmacodynamics, kinetics
Clinical use and dosing
Adverse effects/safety
Recommended reading
Chapter 3: Histamine H2-receptor antagonists
Introduction
Mechanism of action
Pharmacology
Clinical effectiveness
Adverse events
Recommended reading
Chapter 4: Prostaglandins and other mucosal protecting agents
Introduction of drug class
Physicochemical properties
Formulations and recommended dosages
Mechanism of action
Drug interactions
Pharmacokinetics
Clinical effectiveness
Toxicity
Pregnancy classes
Other mucosal protecting agents
Recommended reading
PART II: SMALL AND LARGE INTESTINE
Chapter 5: 5-HT modulators and other antidiarrheal agents and cathartics
Introduction
5-HT modulators used in the management of GI disorders
5-HT agents approved in the US for specific GI indications
Medications used for the treatment of chronic constipation
Medications used for the treatment of narcotic-induced constipation
Antidiarrheal agents
Conclusion
Recommended reading
Chapter 6: 5-aminosalicylates
Introduction
Preparations
Clinical use and efficacy
Pharmacology: preparations and dosing
Mechanism of action
Bioavailability and metabolism
Adverse effects and toxicity
Pregnancy (Table 6.7)
Drug interactions (package inserts)
Precautions and contraindications (Table 6.8)
Special considerations: effectiveness in colorectal cancer prevention
Conclusion (Table 6.9)
Recommended reading
Chapter 7: Immunosuppressive agents
Introduction
Thiopurines
Low-dose methotrexate (MTX)
Calcineurin inhibitors
Recommended reading
Chapter 8: Biological agents
Biological agents approved to treat IBD
Optimal treatment strategies with anti TNF therapies in IBD
Safety of biological agents in IBD
Emerging biologicals
Recommended reading
PART III: LIVER AND PANCREAS
Chapter 9: Interferons
Introduction
Mechanism of action
Pharmacology
Clinical effectiveness
Toxicity
Interferon types with generic and brand names
Pregnancy classes
Initial interferon dosing regimens for chronic hepatitis C
Recommended reading
Chapter 10: Nucleoside analogs
Introduction
Mechanism of action
Pharmacology
Clinical effectiveness
Nucleoside analogs
Nucleotide analogs
Summary
Recommended reading
Chapter 11: Ursodeoxycholic acid, chelating agents, and zinc in the treatment of metabolic liver diseases
Ursodeoxycholic acid
Treatment of copper overload
Recommended reading
Chapter 12: Agents for the treatment of portal hypertension
Introduction
Nonselective beta-blockers (NSBB)
Nitrates
Vasopressin analogs
Somatostatin analog
Midodrine
Albumin
Loop diuretics
Aldosterone antagonist
Aquaretics
Disaccharides
Antibiotics
Recommended reading
Chapter 13: Pancreatic enzymes
Introduction
Mechanism of action
Dosing and schedule of administration
Monitoring therapy
Adverse effects
Recommended reading
PART IV: ANTIMICROBIALS AND VACCINES
Chapter 14: Antibiotics for the therapy of gastrointestinal diseases
Introduction
Pharmacologic properties
Clinical uses
Recommended reading
Chapter 15: Antimicrobials for parasitic diseases
5-Nitroimidazoles
Benzimidazoles
Ivermectin
Praziquantel
Treatment dosages (Table 15.3)
Recommended reading
Chapter 16: Vaccines for viral hepatitides
Hepatitis A vaccination
Hepatitis B vaccination (Table 16.1)
Recommended reading
Chapter 17: Rotavirus and other enteric vaccinations
Rotavirus vaccination
Typhoid fever vaccination
Recommended reading
PART V: NUTRITION AND PROBIOTICS
Chapter 18: Parenteral and enteral nutrition feeding formulas
Introduction
Indications for nutrition support
Energy and macronutrient requirements
Protein
Carbohydrate
Lipids
Enteral liquid feeding formulations
Disease-specific formulas
Selection of an appropriate enteral formula
Implementation of enteral nutrition
Parenteral nutrition
Summary
Recommended reading
Chapter 19: Probiotics
Introduction
Pharmacology
Mechanisms of action
Clinical indications (Table 19.2)
Safety/toxicity
Summary
Recommended reading
Index
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Library of Congress Cataloging-in-Publication Data
Pocket guide to gastrointestinai drugs / edited by M. Michael Wolfe, Robert C. Lowe.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-118-48157-8 (paperback)
I. Wolfe, M. Michael, editor of compilation. II. Lowe, Robert C., 1966- editor of compilation.
[DNLM: 1. Gastrointestinal Agents–therapeutic use–Handbooks. 2. Gastrointestinal Agents–pharmacology–Handbooks. 3. Gastrointestinal Diseases–drug therapy–Handbooks. QV 39]
RM365
615.7′3–dc23
2013041991
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover image: iStock #10849434 © Mordolff
Cover design by Meaden Creative
List of contributors
Uri Avissar, MD
Boston Medical Center
Assistant Professor of Medicine
Boston University School of Medicine
Boston, MA, USA
Samra S. Blanchard, MD
Associate Professor
Division Head, Pediatric Gastroenterology and Nutrition
University of Maryland School of Medicine
Baltimore, MD, USA
Wanda P. Blanton, MD
Assistant Professor of Medicine
Section of Gastroenterology
Boston Medical Center
Boston University School of Medicine
Boston, MA, USA
Andrew K. Burroughs, MB. BCh Hons, FEB, FEBTM, Hon DSc (Med), FRCP, FMedSci
Consultant Physician and Hepatologist
The Royal Free Sheila Sherlock Liver Centre
Royal Free London NHS Foundation Trust;
Professor of Hepatology
Institute for Liver and Digestive Health
University College London
London, UK
Andrés Cárdenas, MD, MMSc, AGAF
Faculty Member and Senior Specialist
Institute of Digestive Diseases and Metabolism
University of Barcelona
Hospital Clinic
Barcelona, Spain
Raymond T. Chung, MD
Director of Hepatology, Medicine Service
Massachusetts General Hospital;
Associate Professor of Medicine
Harvard Medical School
Boston, MA, USA
Steven J. Czinn, MD
Professor and Chair, Department of Pediatrics
University of Maryland School of Medicine
Baltimore, MD, USA
James S. Dooley, BSc, MB, BS, MD, FRCP
Emeritus Reader in Medicine
Institute for Liver and Digestive Health
University College London;
Consultant Hepatologist
The Royal Free Sheila Sherlock Liver Centre
Royal Free London NHS Foundation Trust
London, UK
Douglas Drossman, MD
Adjunct Professor of Medicine and Psychiatry
University of North Carolina;
Co-director Emeritus
University of North Carolina Center for Functional GI and Motility Disorders
Drossman Center for the Education and Practice of Biopsychosocial Care
Chapel Hill, NC, USA
Francis A. Farraye, MD, MSc
Clinical Director, Section of Gastroenterology
Boston Medical Center;
Professor of Medicine
Boston University School of Medicine
Boston, MA, USA
Ronnie Fass, MD
Professor of Medicine Care, Western Reserve University;
Director, Division of Gastroenterology and Hepatology
Head, Esophageal and Swallowing Center
MetroHealth Medical Center
Cleveland, OH, USA
Gerald M. Fraser, MD, FRCP
Associate Professor of Medicine
Director, Inflammatory Bowel Disease Unit
Division of Gastroenterology
Rabin Medical Center
Beilinson Hospital
Petah Tikva;
Sackler Faculty of Medicine
Tel-Aviv University
Tel-Aviv, Israel
Albena Halpert, MD
Assistant Professor of Medicine
Section of Gastroenterology
Boston Medical Center
Boston University School of Medicine
Boston, MA, USA
Esther Jacobowitz Israel, MD
Assistant Professor, Pediatrics Harvard Medical School;
Director, Inpatient Quality and Safety
Associate Chief, Pediatric Gastroenterology and Nutrition
Mass General Hospital for Children
Boston, MA, USA
Savio John, MBBS
Assistant Professor of Medicine
SUNY Upstate
Syracuse, NY, USA
Hemangi Kale, MD
Assistant Professor of Medicine
Case Western Reserve University;
Fellowship Program Director
Division of Gastroenterology and Hepatology
MetroHealth Medical Center
Cleveland, OH, USA
Karen L. Krok, MD
Associate Professor of Medicine
Penn State Milton S. Hershey Medical Center
Hershey, PA, USA
Angel Lanas, MD, PhD
Chair, Digestive Diseases Service
University Hospital, IIS Aragón
University of Zaragoza, CIBERehd
Zaragoza, Spain
Lev Lichtenstein, MD
Senior Physician
Inflammatory Bowel Disease Unit
Division of Gastroenterology
Rabin Medical Center
Beilinson Hospital
Petah Tikva, Israel
Robert C. Lowe, MD
GI Fellowship Director
Boston Medical Center;
Associate Professor of Medicine
Boston University School of Medicine
Boston, MA, USA
Hannah L. Miller, MD
Assistant Professor of Medicine
Section of Gastroenterology
Boston Medical Center
Boston University School of Medicine
Boston, MA, USA
Christopher J. Moran, MD
Instructor in Pediatrics
Harvard Medical School;
Assistant in Pediatrics
Mass General Hospital for Children
Boston, MA, USA
David P. Nunes, MD
Director of Hepatology
Boston Medical Center;
Associate Professor of Medicine
Boston University School of Medicine
Boston, MA, USA
Melissa Osborn, MD
Associate Professor of Medicine
Division of Infectious Diseases
MetroHealth Medical Center
Case Western Reserve University
Cleveland, OH, USA
Dominic N. Reeds, MD
Assistant Professor of Medicine
Division of Geriatrics and Nutritional Science
Washington University School of Medicine
St. Louis, MO, USA
Joachim Richter, MD
Adjunct Professor of Tropical Medicine
University Hospital for Gastroenterology, Hepatology and Infectious Diseases
Heinrich-Heine-University
Düsseldorf, Germany
Carlos Sostres, PhD
Research Faculty
Digestive Disease Service
University Hospital, IIS Aragón
Zaragoza, Spain
Kentaro Sugano, MD
Chief Professor, Division of Gastroenterology
Department of Medicine
Jichi Medical University
Shimotsuke, Tochigi, Japan
Christina M. Surawicz, MD
Professor of Medicine
Department of Medicine
Division of Gastroenterology
Washington University School of Medicine
Seattle, WA, USA
Beth Taylor MS, RD, CNSC, FCCM
Nutrition Support Specialist
Barnes-Jewish Hospital
St. Louis, MO, USA
Gert Van Assche, MD, PhD
Professor of Medicine
University of Leuven
Leuven, Belgium;
Division of Gastroenterology
University of Toronto;
Division of Gastroenterology
Mount Sinai Hospital
Toronto, ON, Canada
M. Michael Wolfe, MD
Chair, Department of Medicine
MetroHealth Medical Center;
Charles H. Rammelkamp, Jr. Professor of Medicine
Case Western Reserve University School of Medicine
Cleveland, OH, USA
Preface
In the mid-1970s, Sir James Black developed the first H2-receptor antagonist, cimetidine, a remarkable achievement that revolutionized the treatment of acid-peptic disorders and led to the awarding of his Nobel Prize in Medicine. One year after its approval by the US Food and Drug Administration in 1977, cimetidine became the most widely prescribed drug in the world. Three other H2-receptor antagonists were subsequently marketed worldwide, and in the late 1980s, the first proton pump inhibitor omeprazole was approved for use and likewise became the most prescribed drug worldwide. Since that time, there has been a virtual explosion in the number of pharmaceutical agents available for the treatment of gastrointestinal diseases, from new biologic immunomodulators for inflammatory bowel disease to novel antiviral agents for the treatment of hepatitis B and C.
This handbook has been carefully formulated and written to provide the busy clinician with a concise, yet scholarly, review of the major classes of drugs used in the treatment of gastrointestinal and hepatobiliary disorders. Each chapter discusses the pharmacology and clinical effectiveness of classes of medications, including indications for use, dosing, and adverse events. The outstanding group of authors who have contributed their wisdom and experience represent academic centers from around the world, with contributions from Europe, Asia, and North America. The authors were selected primarily for their record of excellence as investigators, clinicians, and educators. All are engaged in clinical or basic investigation and are particularly proficient in the application of basic scientific information to the realm of patient management.
The target audience for this handbook includes gastroenterologists, gastrointestinal surgeons, and all physicians who care for patients afflicted with digestive disorders. The authors have used great care and discrimination in presenting their materials, and the subject matter has been composed in a concise, yet thorough, format. Accordingly, medical students, internal medicine, family medicine, and surgery residents, and gastroenterology fellows will view this guide as an invaluable adjunct to their educational needs, and it should be regarded as useful to the practices of emergency room and primary care physicians, hospitalists, intensivists, pharmacists, and other health care providers involved in the management of diseases of the gastrointestinal tract and hepatobiliary systems. While generic drug names are used throughout the text, each chapter also lists the international trade names for each drug to enable rapid identification of each agent.
We, the editors, dedicate this book to our colleagues and trainees, whose contributions to clinical care, research, and teaching have made our academic careers intellectually challenging and personally rewarding. We also thank Claire Brewer and Oliver Walter at Wiley, who approached the formidable task of publishing this handbook with the utmost care and who provided immeasurable assistance and advice throughout the course of formulating the content and producing the final product.
M. Michael Wolfe and Robert C. Lowe
PART: I
UPPER GI TRACT
CHAPTER 1
Prokinetic agents and antiemetics
Prokinetics
Introduction
Prokinetic agents enhance coordinated gastrointestinal motility by increasing the frequency and/or the amplitude of contractions without disrupting normal physiological pattern and rhythm of motility.
Acetylcholine is the principle immediate mediator of muscle contractility in the GI tract. However, most clinically useful prokinetic agents act “upstream” of acetylcholine, at receptor sites on the motor neuron itself, or even more indirectly, on neurons that are one or two orders above. Acetylcholine itself is not pharmacologically utilized because it lacks selectivity. It acts on both nicotinic and muscarinic receptors and is rapidly degraded by acetylcholinesterase. Dopamine is present in significant amounts in the GI tract and has an inhibitory effect on motility. It reduces both lower esophageal sphincter basal pressure and intragastric pressure. These effects are mediated by D2 receptors through suppression of acetylcholine release from myenteric motor neurons. Thus, dopamine receptor antagonists are effective prokinetic agents because of antagonizing the inhibitory effect of dopamine on myenteric motor neurons. Additionally, they act centrally on the chemoreceptor trigger zone (CTZ), thereby relieving nausea and vomiting. Presently, very few prokinetics are available in the market, primarily due to the failure of many of these compounds to demonstrate significant symptom improvement when compared with placebo in pivotal indication trials. In addition, these agents have an unacceptable safety profile. The exact reasons for the former are unknown but are believed to be related to disassociation between severity and/or frequency of symptoms and the severity or even the presence or absence of a motility abnormality.
Metaclopramide (Reglan)
Metaclopramide is indicated for the prophylaxis of chemotherapy-associated nausea and vomiting (second line agent); diabetic gastroparesis; gastroesophageal reflux disease (GERD); prior to endoscopic or radiologic exam, to place a feeding tube beyond the pylorus; and postoperative nausea and vomiting. Metaclopramide is also commonly used, but not FDA approved in, nondiabetic gastroparesis, hyperemesis gravidarum, and dyspepsia.
Mechanism of action
The drug works through several mechanisms. It is a dopamine receptor antagonist, a 5-HT3 antagonist, and a 5-HT4 agonist. It also blocks serotonin receptors in the chemoreceptor trigger zone of the central nervous system (CNS). Metaclopramide enhances the response to acetylcholine in the upper GI tract, resulting in coordinated contractions and thus accelerated gastric emptying, as well as increasing lower esophageal sphincter tone.
Pharmacology
Metaclopramide is absorbed rapidly after oral ingestion, metabolized by the liver and is excreted principally in the urine with a t ½ of 4–6 hours. The onset of action after oral administration is 30–60 minutes; after IV administration, 1–3 minutes; and after IM administration, 10–15 minutes. Dosing of metaclopramide for each different indication is listed in Table 1.1. The bioavailability of different medications may be affected due to accelerated gastric emptying. Drugs with narrow therapeutic indices need to be monitored closely when administered concomitantly with metoclopramide. The concomitant administration of CNS depressants, such as anxiolytics, hypnotics or sedatives, as well as alcohol, with metoclopramide can possibly increase sedation. The concomitant administration of metoclopramide with drugs that can cause extrapyramidal reactions is contraindicated. Patients with hepatic impairment do not need dosage adjustment. In addition, patients with mild renal impairment (CrCl ≥40 ml/minute) do not require a dosage adjustment. However, patients with CrCl <40 ml/minute require a dose reduction of 50%.
Indications | Adult dosage | Child dosage |
Diabetic gastroparesis | Oral: 10 mg 30 minutes before each meal and bedtime for 2–8 weeks
Parenteral: IV/IM: 10 mg if oral route is not available |
|
IV infusion for chemotherapy-induced emesis | 1–2 mg/kg administered over 15 minutes, beginning 30 minutes prior to chemotherapy and repeated as needed every 2–3 hrs | 1–2 mg/kg administered over 15 minutes, beginning 30 minutes prior to chemotherapy and repeated as needed every 2–3 hrs |
Post-operative nausea/vomiting and nausea vomiting prophylaxis | 10 mg IM or IV near end of the surgical procedure, repeat every 4–6 hrs as needed | 0.1–0.2 mg/kg IV, repeat every 6–8 hrs as needed |
Gastroesophageal reflux disease (GERD) | 10–15 mg orally up to 4 times/day. Therapy – recommended no more than 12 weeks | Child/infant: 0.1 mg/kg orally 3–4 times/day
Neonates: 0.15 mg/kg orally every 6 hrs |
Prior to endoscopic or radiologic procedures | 10 mg IV | <6 years: 0.1 mg/kg IV single dose;
6–14 years: 2.5_5 mg IV |
Adverse effects
Major side effects due to central dopamine antagonism include extrapyramidal reactions, such as acute dystonic attack, pseudo-parkinsonism, akathisia, tardive dyskinesia, and rarely neuroleptic malignant syndrome. Parkinson-like symptoms occur several weeks after the initiation of therapy and usually subside 2–3 months after the discontinuation of therapy. Tardive dyskinesia can occur after weeks to years of therapy initiation and may be irreversible. It appears to be more common in elderly patients. Strategies such as titrating to lowest effective dose and drug holidays may decrease these side effects. Patients should be warned to inform their physician if any involuntary movements develop. Rarely, cardiac arrhythmias, hypersensitivity reactions, hyperprolactinimia, impotence and neuroleptic malignant syndrome have all been reported.
Motilin agonists
Motilin, a peptide hormone found in the GI M cells and some enterochromaffin cells, is a powerful contractile agent of the upper gastrointestinal (GI) tract. Erythromycin and other macrolide antibiotics like azithromycin and clarithromycin mimic the molecular structure of motilin and thus are potent promotility agents. Rapid development of tolerance and side effects, as well as concerns about using antibiotics long term, limits the use of these drugs as prokinetics. Intravenous erythromycin may be used to “restart or kick-start” the stomach during acute episodes of gastroparesis. It has also been used to clear the stomach prior to endoscopy of patients with an upper gastrointestinal bleed.
Pharmacology
The standard dose of erythromycin for gastric stimulation is 3 mg/kg IV or 200–250 mg orally every 8 hours and for azithromycin 250 mg daily. For small intestinal motility, a lower dose of 40 mg IV is more commonly used. However, the drugs are contraindicated in concomitant use with astemizole, dihydroergotamine, ergotamine, pimozide, terfenadine and in patients with known hypersensitivity to motilides. In elderly patients with renal/hepatic impairment, there is an increased risk of hearing loss, hepatotoxicity and QT prolongation. Lastly, erythromycin has been designated as Pregnancy Category B.
Adverse effects
Gastrointestinal toxicity (nausea, anorexia, diarrhea, abnormal liver enzymes and jaundice), bacterial resistance, pseudomembranous colitis and sudden cardiac death due to prolonged QT interval syndrome have all been well documented. Azithromycin has similar effects on GI motility as the other macrolides but was originally thought to lack drug interaction that can lead to prolonged QT interval. However, the FDA recently issued a warning that azithromycin can lead to fatal arrhythmia in certain patients. The extent of the risk is unknown. The macrolides require adjustment in patients with hepatic impairment because of the possibility of accumulation, whereas in patients with renal impairment, no need for dose adjustment is necessary.
Bethanechol
Bethanechol is a prokinetic agent that improves GI motility by acting as a cholinergic agonist, releasing acetylcholine from nerve endings. The drug is less commonly used today as a prokinetic due to its high rate of cholinergic-related adverse events and poor patient tolerability. While not specifically indicated for GI-related disorders, the drug has been used in GERD, primarily in patients who are refractory to proton pump inhibitor (PPI) treatment. The dosing is 25 mg orally four times a day. Bethanechol is contraindicated in patients with asthma and bradycardia. Its adverse effects are primarily related to its cholinergic effects and consequently also include syncope, dizziness, diarrhea, and urgent desire to urinate. Bethanechol is designated as Pregnancy Category C.
Domperidone
The drug is not FDA approved but is available in many countries outside the US, including Mexico and Canada. It is a peripheral dopamine D2 receptor antagonist. It does not readily cross the blood brain barrier (BBB) and is hence less likely to cause extrapyramidal side effects. It can affect CNS areas that lack this barrier and those areas involved in temperature control, prolactine release and emesis. The drug is used for gastroparesis and GERD. The drug is dosed 10 to 20 mg three times a day.
Antiemetic agents
Introduction
Nausea (Latin nausea, from Greek vauoia, nausie, “motion sickness,” “feeling sick,” queasy” or “wamble”) is a sensation of unease and discomfort in the upper abdomen, which often leads to vomiting. Vomiting, an act of forceful expulsion of stomach contents, is a complex process, consisting of coordination between central and peripheral mechanisms. Vomiting is coordinated by a central emesis center in the lateral reticular formation of the mid brainstem that is adjacent to both the chemoreceptor trigger zone (CTZ) in the area postrema (AP) at the base of the forth ventricle and the solitary tract nucleus (STN) of the vagus nerve. The absence of a BBB allows the CTZ to monitor blood and cerebrospinal fluid constantly for toxic substances and to relay information to the emesis center. It also receives input from the vagus nerve via the STN, splanchnic afferents via the spinal cord, the cerebral cortex and the vestibular apparatus. CTZ has high concentration of 5-HT3, dopamine and opioids receptors, while the STN is rich in enkephalin, histamine, acetylcholine and 5-HT3 receptors.
Antiemetics are classified according to the predominant receptor on which they are proposed to act. However, the mechanisms of action may overlap among the different antiemetics. Data comparing antiemetics in specific disorders is very limited; hence drug selection in a particular situation is empiric, based on preferred route of administration, safety and personal experience.
Five neurotransmitter receptor sites have been identified that play an important role in the vomiting reflex: muscarinic (M1), dopamine (D2), histamine (H1), serotonin (5-HT3), and Substance P/Neurokinin Receptor 1. Consequently, antiemetics were primarily developed as inhibitors of these receptors (Tables 1.2, 1.3 and 1.4). This chapter will not cover the serotonin-related products, which are discussed elsewhere in this book.
Antiemetic class | Medications | Common therapeutic utilization |
5-HT3 antagonist | Ondansetron (Zofran)
Granisetron (Kytril) Dolasetron (Anzemet) Palonosetron (Aloxi) |
Chemotherapy-induced nausea and vomiting prophylaxis Radiation-induced nausea and vomiting prophylaxis
Postoperative nausea and vomiting prophylaxis |
D2 antagonist | Metoclopramide (Reglan)
Prochlorperazine (Compazine) Trimethobenzamide (Tigan) Droperidol (Inapsine) |
Chemotherapy-induced nausea and vomiting
Motion sickness Postoperative nausea and vomiting |
H1 receptor antagonist | Cyclizine (Bonine for children, Marezine)
Promethazine (Phenergan) Hydroxyzine (Atarax, Vistaril) Meclizine (Antivert, Bonine, Dramamine, Zentrip, VertiCalm) |
Motion sickness
Postoperative nausea and vomiting prophylaxis |
M1 antagonist | Hyoscine (Scopolamine) | Motion sickness |
NK1 antagonist | Aprepitant (Emend)
Fosaprepitant (Emend Inj) |
Chemotherapy-induced nausea and vomiting |
Cannabinoids | Dronabino (Marinol)
Nabilone (Cesamet) |
Chemotherapy-induced nausea and vomiting |
Dopamine receptor antagonists
Three classes of dopamine receptor antagonists are currently available. They include phenothiazines: prochlorperazine (Compazine), chlorpromazine (Thorazine); butyrophenones: droperidol (Inaspine), haloperidol (Haldol); and benzamides: metoclopramide (Reglan), Domperidone (Motilium) and trimethobenzamide hydrochloride (Tigan).
Phenothiazines
The phenothiazines are the most commonly used antiemetics. These drugs are moderately effective for nausea caused by various GI and non-GI disorders and in mild to moderate, but not highly emetogenic, chemotherapy. Prochlorperazine (Compazine) predominantly blocks D2 dopamine receptors in the area postrema, but also possesses muscarinic (M1) and histamine (H1) antagonist effects. Prochlorperazine is indicated for severe nausea and vomiting. Although not indicated, it is also used in chemotherapy–induced nausea and vomiting. The drug is contraindicated in children under 2 years of age, comatose states, and in patients with hypersensitivity to phenothiazines. The drug should be cautiously used in elderly patients with dementia-related psychosis, adolescents and children with signs suggestive of Reye's syndrome and in those with bone marrow suppression. The adverse effects include hypotension, hypertension, and prolonged QT interval.
Chlorpromazine (Thorazine) is used less often than prochlorperazine. It is a dimethylamine derivative of phenothiazine, whose exact mechanism of action is unknown. It has weak anticholinergic, antihistaminic and antiserotonin activities. The drug is indicated for nausea, vomiting and intractable hiccups. The dosing for nausea and vomiting in the adult is 10–25 mg orally every 4–6 hours and 25 mg IV/IM every 3–4 hours. In the pediatric population, the dose is 0.25 mg/lb orally and 0.125 mg/lb IM. Chlorpromazine is contraindicated in a comatose state, concomitant use of large doses of CNS depressants and in those with hypersensitivity to the drug. Administration in elderly patients with dementia-related psychosis or those with bone marrow suppression should be cautiously done. Adverse effects include akathesia, dizziness, tardive dyskinesia, and constipation. In patients with hepatic impairment, a lower dose should be considered. In contrast, in patients with renal impairment, there is no need for dose adjustment. The drug has been designated Pregnancy Category C.
Butyrophenones
The butyrophenones are used for procedural sedation as preanaesthetic agents and for post-operative nausea and vomiting. They are tranquilizers that potentiate action of opioids and have antiemetic effect when used alone.
The exact mechanism of action of droperidol (Inapsine) is unknown. Its antiemetic effect may be due to binding of GABA receptors in the CTZ. It antagonizes the action of dopamine by binding to D2 receptors centrally. The drug is indicated for nausea and vomiting associated with surgical or diagnostic procedures and for prophylaxis of nausea/vomiting. The drug is not indicated, but is commonly used, for nausea and vomiting due to other reasons and for chemotherapy-induced vomiting. Droperidol is contraindicated in patients with hypersensitivity to the drug or those with prolonged QT interval. In those patients with other arrythmogenic medications, elderly patients, and in patients with renal or hepatic impairment, the drug should be used with caution. Adverse effects include prolonged QT interval, torsades de pointes, ventricular tachycardia, cardiac arrest, hypertension, and somnolence. In patients with hepatic impairment, lower doses may be required. Similarly, in patients with renal impairment, lower doses are required.
Benzamides
The benzamides include metoclopramide and domperidone, which are discussed earlier in this chapter.
Trimethobenzamide hydrochloride (Tigan) is a dopamine receptor antagonist that is indicated for nausea due to gastroenteritis and for postoperative nausea and vomiting. The drug is contraindicated in patients with previous hypersensitivity to the drug and in patients in the pediatric age group. Elderly patients may have an increased risk of extrapyramidal and CNS side effects. Adverse effects include hypotension, xerostomia, diarrhea, anticholinergic adverse reactions, and somnolence. A decrease in the total daily dose or frequency of administration should be considered in patients with diminished renal function, defined as a CrCl # 70 ml/minute. In those with hepatic impairment, there is no need for dose adjustment. In pregnant women, fetal risk cannot be ruled out.
Histamine 1 receptor antagonists
The antihistaminics are histamine 1 (H1) receptor antagonists that are primarily useful for motion sickness and post-operative emesis. Their precise mechanism of action is not known, but may be due to a direct effect on the labyrinthine apparatus, as well as central action on CTZ.
Cyclizine (Marezine) is indicated in adults for nausea and vomiting due to motion sickness and should be taken 30 minutes prior to travel time. It is also indicated in the pediatric population for postoperative vomiting. The dose for those aged 6–12 years is 25 mg every 6–8 hours, not to exceed 75 mg/24 hours. For those older than 12 years, the dose is 50 mg every 4–6 hours, not to exceed 200 mg/24 hours. In patients with postoperative nausea who are between the ages of 6–10 years, the dose is 3 mg/kg/day in three divided doses IM or orally. The drug is contraindicated in patients with known hypersensitivity to the drug. In subjects with asthma, COPD, glaucoma, congestive heart failure (CHF), obstructive uropathy and epilepsy, caution should be taken when using the drug. Adverse effects include drowsiness, dizziness, dry mucous membranes, pancytopenia, arrhythmias, and heat stroke.
Hydroxyzine (Atarax, Vistaril) is indicated for motion sickness. In patients with renal impairment (CrCl <50), the dose should be decreased by 50%, while in those with hepatic impairment, the frequency of administration should be decreased. Another member of the antihistaminics family is promethazine (Phenergan). The drug is indicated for nausea/vomiting and for motion sickness. Dose adjustments have not been defined in patients with renal or hepatic impairment.
Meclizine (Antivert, Bonine, Dramamine, Zentrip), another H1 antagonist, is used for non-GI related indications, but also for motion sickness.
Anticholinergic agents
Scopolamine is a belladonna alkaloid that possesses anticholinergic properties. It functions as an M1-muscarinic antagonist by blocking cholinergic transmission from the vestibular nuclei. The drug is indicated for motion sickness and postoperative nausea and vomiting (1.5 mg transdermal patch). Scopolamine is contraindicated in COPD, liver impairment and in patients with tachyarrythmia. Adverse effects include xerostomia, blurred vision, and somnolence.
Neurokinin receptor antagonists
Aprepitant (Emend) and fosaprepitant (Emend Injection) are selective high affinity antagonists of human substance P/neurokinin 1 (NK1). In animal models, they appear to work at the cerebral cortex and dorsal raphae. By inhibiting the substance P/neurokinin 1 receptor, they prevent acute and delayed vomiting. They are indicated for chemotherapy-associated nausea and vomiting due to highly and moderately emetogenic chemotherapy, nausea and vomiting prophylaxis and post-operative nausea and vomiting prophylaxis.
Aprepitant (Emend) is dosed for chemotherapy-induced nausea and vomiting prophylaxis at 125 mg orally 1 hour prior to chemotherapy on day 1 followed by 80 mg orally daily in the morning on days 2 and 3 (used in combination with corticosteroids/5-HT3 antagonist as per treatment protocol). In postoperative nausea-vomiting prophylaxis, the drug is dosed at 40 mg orally once, 3 hours prior to anesthesia.
Fosaprepitant (Emend Injection) is dosed for chemotherapy-induced nausea and vomiting as a single-dose regimen, a single dose of 150 mg IV started 30 minutes prior to chemotherapy on day 1 or as a three-day regimen. An alternate regimen includes a single dose of fosaprepitant 115 mg IV, followed by aprepitant 80 mg orally for 2 days, which is started 30 minutes prior to chemotherapy. The drug is contraindicated in patients with hypersensitivity to the medication and those with severe liver impairment. Adverse effects may include neutropenia, bradycardia, and Stevens Johnson syndrome. In hepatic impairment, there is no dose adjustment for Child-Pugh A and B. However, it is not yet defined for C. There is no need for dose adjustment in renal impairment.
Cannabinoids
The exact mechanism of action of cannabinoids is not known, although they bind to cannabinoid receptors in the neural tissues. Dronabinol is indicated in chemotherapy-induced nausea and vomiting prophylaxis. The drug is dosed in adults at 5 mg/m2 orally 1–3 hours before chemotherapy and 5 mg/m2 orally every 2–4 hours after chemotherapy for total of 4–6 doses/day. The dose may be increased by 2.5 mg/m2 to a maximum of 15 mg/m2/dose. Nabilone7 is dosed in the adult at 1–2 mg orally 2–3 times a day, 1–3 hours prior to chemotherapy. The drug may be given the night before chemotherapy (1–2 mg). The maximum is 6 mg a day. Both drugs are not recommended to patients below age 18. They are contraindicated in those with hypersensitivity to dronabinol, cannabinoids and sesame oil. They should be used cautiously in patients with a history of alcohol abuse, seizure disorder and psychiatric illness. Adverse effects include tachyarrythmia, abdominal pain, amnesia and ataxia. No need for dose adjustments in patients with either hepatic or renal impairment.
Recommended reading
Glare PA, Dunwoodie D, Clark K, Ward A, Yates P, Ryan S, Hardy JR (2008) Treatment of nausea and vomiting in terminally ill cancer patients. Drugs 68(18): 2575–90.
Hasler WL (2008) Management of gastroparesis. Expert Rev Gastroenterol Hepatol June; 2(3): 411–23.
Hejazi RA, McCallum RW, Sarosiek I (2012) Prokinetics in diabetic gastroparesis. Curr Gastroenterol Rep Aug.; 14(4): 297–305.
A comprehensive review on the topic diabetic gastroparesis that also includes our present knowledge about prokinetics, antiemetics and future drug development.
Karamanolis G, Tack J (2006) Promotility medications – now and in the future. Dig Dis 24(3–4): 297–307.
An excellent review on the currently available prokinetics, as well as those that presently are undergoing clinical evaluation.
Olden KW, Chepyala P (2008) Functional nausea and vomiting. Nat Clin Pract Gastroenterol Hepatol Apr.; 5(4): 202–8.
Reddymasu SC, Soykan I, McCallum RW (2007) Domperidone: review of pharmacology and clinical applications in gastroenterology. Am J Gastroenterol 102(9): 2036–45.
A nice review with a specific focus on domperidone, which includes pharmacology, clinical application and safety profile of the drug.
Sawhney MS, Prakash C, Lustman PJ, Clouse RE (2007) Tricyclic antidepressants for chronic vomiting in diabetic patients. Dig Dis Sci Feb.; 52(2): 418–24.
Stapleton J, Wo JM (2009) Current treatment of nausea and vomiting associated with gastroparesis: antiemetics, prokinetics, tricyclics. Gastrointest Endosc Clin N Am Jan.; 19(1): 57–72.
Another comprehensive review of antiemetics and prokinetics in the treatment of gastroparesis. It also discusses the role of tricyclics in the treatment of nausea and vomiting.
Steele A, Carlson KK (2007) Nausea and vomiting: applying research to bedside practice. AACN Adv Crit Care 18(1): 61–73.