Pocket Guide to GastrointestinaI Drugs

M. Michael Wolfe, Robert C. Lowe, M. Michael Wolfe, Robert C. Lowe

• Publisher: Wiley-Blackwell
• Year: 2014
• Print ISBN: 9781118481578
• eBook ISBN: 9781118481554
• Edition: 1
• Topic: Medicine
• Subtopic: Gastroenterology & Hepatology

Learn all you need to know about gastrointestinal drugs and their clinical use with this one-stop, rapid reference pocket guide.

Brought to you by many of the world's leading GI drug experts, Pocket Guide to Gastrointestinal Drugs provides comprehensive guidance to the pharmacological properties of drugs used to treat gastrointestinal conditions, including mechanisms of action, appropriate administration, and potential adverse effects associated with their use.

Organized by class of drug and ranging from PPIs to immunosupressants, each chapter first examines the specific agents within that class and then their appropriate and judicious use across a range of specific GI disorders.

Key features include:

• Introduction of drug class
• Basic pharmacology, including mechanism of action, bioavailability, metabolism, interactions, adverse effects, toxicity, and special considerations
• Dosing information for each GI condition and on- and off-label use
• Consistent use of both generic and trade names throughout
• Specific reference to drug use in pediatric patients and during pregnancy

Perfect for quick consultation on the wards and in the office, Pocket Guide to Gastrointestinal Drugs is the ideal tool for all those managing patients with GI conditions, including gastroenterologists, GI trainees, emergency physicians, GI specialist nurses, primary care physicians and residents, intensivists and pharmacists.

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PART: I

UPPER GI TRACT

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CHAPTER 1

Prokinetic agents and antiemetics

Hemangi Kale and Ronnie Fass

MetroHealth Medical Center, Cleveland, OH, USA

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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%.

Table 1.1 Dosing and route of administration of metaclopramide (Reglan)

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 ha...

Table of contents

• Cover
• Title Page
• Copyright
• List of contributors
• Preface
• PART I: UPPER GI TRACT
• PART II: SMALL AND LARGE INTESTINE
• PART III: LIVER AND PANCREAS
• PART IV: ANTIMICROBIALS AND VACCINES
• PART V: NUTRITION AND PROBIOTICS
• Index