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%.
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
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