Gastrointestinal Pro Kinetic Theraphy-dopaminergic Antagonist Drugs

V Continuing Education Article

Vol.19, No. 2 February 1997

N E W ! C O N T I N U I N G E D U C AT I O N S E R I E S Successfully complete the quizzes at the end of each CE article in this series, and receive a certificate suitable for framing. This is the first of five articles.

FOCAL POINT ★Metoclopramide and domperidone stimulate motility of the proximal gastrointestinal tract—the gastroesophageal sphincter, stomach, and small intestine.

Gastrointestinal Prokinetic Therapy: Dopaminergic Antagonist Drugs

KEY FACTS ■ Metoclopramide (0.2 to 0.5 mg/kg every 8 hours orally) is more potent than domperidone as a proximal gastrointestinal prokinetic agent. ■ Metoclopramide and domperidone stimulate gastrointestinal motility via mechanisms other than dopaminergic receptor antagonism—such as 5-HT3 receptor antagonism, 5-HT4 agonism, and indirect cholinergic effects. ■ Delayed gastric emptying is best managed by means of liquid feedings, carbohydrate-enriched diets, and metoclopramide. ■ Domperidone (0.05 to 0.10 mg/kg orally every 12 to 24 hours) is more potent than metoclopramide as an antiemetic agent.

Oregon State University

University of Pennsylvania

Jean A. Hall, DVM, PhD

Robert J. Washabau, VMD, PhD

T

he dopaminergic antagonists are a group of drugs with gastrointestinal prokinetic and antiemetic properties. These agents inhibit peripheral and/or central dopamine receptors. Metoclopramide and domperidone, for example, reverse the gastric relaxation induced by dopamine infusion in dogs,1 and they abolish the vomiting associated with apomorphine therapy.2 Although the role of dopamine receptors in chemoreceptor trigger zone– induced vomiting is fairly well established,3,4 there is no definite evidence that inhibitory dopaminergic neurons regulate gastrointestinal motility. The prokinetic effects of metoclopramide and domperidone thus may not be readily explained by dopamine receptor antagonism. Some dopaminergic antagonists (e.g., metoclopramide) have been demonstrated to have other pharmacologic properties (e.g., 5-HT3 [5-hydroxytryptamine3] receptor antagonism5 and 5HT4 receptor agonism6). Other dopaminergic antagonists (e.g., domperidone) have been demonstrated to exhibit α2- and β2-adrenergic receptor antagonism7,8 (Figure 1). The characterization of these drugs as dopaminergic antagonists thus may not properly describe their in vivo effects. This is Part I of a five-part presentation on gastrointestinal prokinetic therapy. The remaining parts will consider the following four topics, respectively: motilin-like drugs; serotonergic drugs; acetylcholinesterase inhibitors or parasympathetic potentiating drugs; and esophageal, gastric, and colonic motility disorders.

METOCLOPRAMIDE Metoclopramide (2-methoxy-5-chloro-procainamide) has been available in the United States since the 1970s and is used as a gastrointestinal prokinetic and antiemetic agent. It is believed to exert its effects via antagonism of dopaminergic D2 receptors and agonism of serotonergic 5-HT4 receptors.

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Physicochemical Properties Metoclopramide hydrochloride is highly soluble in water.9–11 The agent is available as 5- and 10-mg tablets (Reglan®—A. H. Robins), as an orangecolored syrup (1 mg/ml), and for injection at 5 mg/ml (2and 10-ml single-dose vials/ampules and 30ml single-dose vials). A 1% aqueous solution stored in a colored container is stable for as long as 5 Figure 1—Diagram of the pharmacologic effects of the gastrointestinal prokinetic agents metoclopramide and domperidone. The release of years.9 acetylcholine from postganglionic cholinergic neurons is enhanced by

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flux of gastric contents from a positivepressure cavity (the stomach) into a negative-pressure conduit (the esophagus). The esophageal mucosa thus is protected from the injurious effects of acid, pepsin, and bile salts. Metoclopramide increases pressure in the lower esophageal sphincter. 12,13 The agent also stimulates gastric emptying in human patients with reflux esophagitis and delayed gastric 14 blockade of presynaptic inhibitory dopamine or α-adrenergic receptors emptying. Delayed Pharmacokinetics and postsynaptic inhibitory β-adrenergic receptors, antagonism of 5-HT3 gastric emptying proMetoclopramide is receptors, or stimulation of 5-HT4 receptors (5-HT3 = ganglionic 5-HT3 motes gastroesophwell absorbed and serotonergic receptor; 5-HT4 = presynaptic 5-HT4 serotonergic receptor; ageal reflux by inrapidly excreted, with D2 = presynaptic D2 dopaminergic receptor; α2 = presynaptic α2-adrener- creasing the gastric a half-life of 60 to 90 gic receptor; ACh = acetylcholine; M3 = postsynaptic M3 muscarinic volume and pressure minutes in dogs. 9 cholinergic receptor; β2 = postsynaptic β2-adrenergic receptor; (–) = inhi- gradient. Diffusion The agent undergoes bition; and (+) = stimulation). (Computer graphics created by Dr. Carl barriers (e.g., sucralfate), low-fat diets, significant first-pass Sammarco, School of Veterinary Medicine, University of Pennsylvania) and avoidance of metabolism; bioavaillate-night meals are integral parts of the treatment of ability is 50% to 70%. It is weakly bound to serum gastroesophageal reflux and reflux esophagitis15; metoproteins, rapidly distributed in most tissues, and highly clopramide is also beneficial in managing the condisoluble in water and ethanol. In the brain, metoclotion. pramide is concentrated in the area postrema, the site of chemoreceptor trigger zone–induced vomiting. The Gastric Emptying major pathway for hepatic metabolism is N-demethylaDelayed gastric emptying, which is a significant cause tion. 9,10 The drug is excreted as the sulfate or gluof upper gastrointestinal tract disorders in dogs and curonide conjugate in bile or is unchanged in urine. cats, is characterized by chronic vomiting.4 Because Impaired renal function prolongs the half-life.9 Resurgical procedures are often unsuccessful, dietary manduced renal clearance makes side effects more likely; agement and gastroprokinetic agents are used to treat the maintenance dosage thus should be decreased to delayed gastric emptying disorders.4 Initially, dietary avoid drug accumulation. management is attempted. Small amounts of a semiThe prokinetic dosage of metoclopramide for use in liquid, low-protein, low-fat diet should be fed at fredogs and cats is 0.2 to 0.5 mg/kg every 8 hours, adminquent intervals. These recommendations are derived istered orally or parenterally. Continuous intravenous from the observations that liquid emptying rates are infusions can be administered at dosages of 0.01 to greater than those for solids and that carbohydrates are 0.02 mg/kg/hr or 1 to 2 mg/kg/day. emptied more rapidly than proteins, which are emptied more rapidly than fats. Drug therapy should be considClinical Applications ered in animals that fail to respond to dietary manageLower Esophageal Sphincter ment alone. In normal physiologic conditions, the lower esophMetoclopramide increases the amplitude and freageal sphincter relaxes to permit passage of food and quency of antral contractions; inhibits fundic receptive fluid into the stomach. This sphincter also prevents reMETOCLOPRAMIDE HYDROCHLORIDE ■ HEPATIC METABOLISM ■ CHRONIC VOMITING

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relaxation; and coordinates gastric, pyloric, and duodenal motility. All of these actions accelerate gastric emptying.16–20 Metoclopramide may be most effective in accelerating the gastric emptying of liquids in dogs.18,19 One study in healthy dogs demonstrated that metoclopramide increased emptying of the liquid phase 1 hour after a meal but had no effect on emptying of the solid phase.18 In another study of healthy dogs, the agent was demonstrated to accelerate the emptying rate of liquids; however, the emptying rate of digestible solids was significantly impaired.19 Metoclopramide had no effect on fed-state gastric motility in dogs after recovery from gastric dilatation–volvulus.21

Small Bowel Motility Studies in humans have demonstrated that metoclopramide increases the rate of gastric emptying and reduces small bowel transit time compared with the effects of a placebo.9 Metoclopramide also enhances antropyloroduodenal coordination in dogs.20 The drug thus may be most effective when delayed gastric emptying results from poor antropyloroduodenal coordination.20 Metoclopramide is less effective in the distal small intestine and colon.22–24 Emesis Metoclopramide inhibits vomiting associated with activation of dopaminergic D2 receptors in the chemoreceptor trigger zone.3,4 The agent thus abolishes vomiting associated with the administration of apomorphine, a dopamine agonist at the chemoreceptor trigger zone. Metoclopramide is also indicated in treating patients with chemotherapy-induced emesis as well as nausea and vomiting associated with delayed gastric emptying, gastroesophageal reflux, and reflux gastritis. Peripherally, metoclopramide may diminish the severity of vomiting via its effects on motility, preventing gastric stasis and the retrograde peristalsis that precedes vomiting. The antiemetic dose of metoclopramide is 1.0 to 2.0 mg/kg/day given as a continuous intravenous infusion. At subcutaneous doses of 1.0 to 3.0 mg/kg, the drug inhibits vomiting associated with cis-platinum chemotherapy; however, significant side effects (e.g., drowsiness, extreme weakness, and body tremors) are occasionally observed.25 Contraindications Metoclopramide should not be used if stimulation of gastrointestinal motility could be harmful (e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation). Because the frequency and severity of seizures or extrapyramidal reactions may be increased, metoclopramide should not be administered

to epileptics or patients receiving other drugs that are likely to cause extrapyramidal reactions.

Pharmacologic Effects Gastrointestinal Effects Metoclopramide has mixed antidopaminergic and cholinergic properties. It antagonizes presynaptic dopaminergic D2 receptors and enhances the release of acetylcholine from postganglionic cholinergic neurons. 26 The exact mechanisms responsible for the gastrointestinal stimulant effects of metoclopramide are unclear. Although metoclopramide antagonizes dopaminergic D2 receptors, the prokinetic effect of metoclopramide probably does not involve dopamine receptors.26 A prejunctional cholinergic mechanism is more likely and may involve 5-HT (serotonin) receptors.27 In the gastrointestinal tract, 5-HT may have direct effects on smooth muscle cells and/or act indirectly by stimulating intramural neurons to release acetylcholine or other neurotransmitters.26,28 The localization of 5-HT in enterochromaffin cells and neurons of the myenteric plexus might account for direct or modulatory effects. Several 5-HT receptor subtypes have been identified throughout the gastrointestinal tract. Metoclopramide antagonizes the 5-HT3 receptor, but the mechanism of gastric prokinesis is probably not related to activity at this receptor.5 Metoclopramide may instead exert its gastric prokinetic effect by stimulating enteric neuronal 5-HT4 receptors.6 Like the 5-HT3 receptor, the 5-HT4 receptor is located presynaptically; when activated, it induces acetylcholine release from the depolarized neuron.6,27–29 The cholinergic effect of metoclopramide thus might be mediated through 5-HT4 receptor–mediated neuronal depolarization. This mechanism may not operate in all animal species or may operate at different sites within a single species.27,30 Extragastrointestinal Effects Metoclopramide is useful as an antiemetic agent because of its antidopaminergic effects at the chemoreceptor trigger zone.3,4 Metoclopramide exhibits all of the effects of a central dopaminergic D2 receptor antagonist: it antagonizes apomorphine-induced abnormal behavior, depresses motor activity, induces catalepsy, and inhibits conditioned behavior. The drug also has pronounced antiemetic activity against the D2 receptor agonist apomorphine.31,32 Adverse Reactions Side effects (which have been reported in as many as 20% of treated humans) are usually mild, transient, and reversible after withdrawal of the drug. These ef-

EMPTYING RATE ■ NAUSEA ■ CHOLINERGIC PROPERTIES

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fects include nervousness, restlessness, listlessness, depression, and dystonic reactions.10 Extrapyramidal side effects are occasionally evident in small animals. Gastrointestinal disorders may be observed. Constipation is commonly associated with long-term use. These complications are probably manifestations of metoclopramide’s antagonism of dopamine-mediated neurotransmission in the central nervous system.

Drug Interactions Atropine and the opioid analgesics may antagonize the action of metoclopramide. Additive sedative effects can occur if metoclopramide is given with narcotics or tranquilizers. Because chronic therapy with phenothiazines can produce side effects similar to those associated with metoclopramide, concomitant use of metoclopramide and phenothiazine drugs should be avoided. In human diabetic patients, metoclopramide influences the delivery of food to the small intestine and thus affects the rate of absorption. In small animals that are receiving insulin, it may be necessary to modify the dosage and timing of therapy. DOMPERIDONE Domperidone is a peripheral dopamine antagonist that acts on dopaminergic D2 receptors in the gastrointestinal tract and chemoreceptor trigger zone.33 Domperidone has prokinetic and antiemetic properties similar to those of metoclopramide, but domperidone does not readily cross the blood–brain barrier.2,34,35 Physicochemical Properties Domperidone is chemically related to the butyrophenones.35 It has been available in most of Europe since the 1980s but has not been marketed in the United States. Domperidone is manufactured as 10-mg tablets, 1- or 10-mg/ml suspension, and 10-, 30-, or 60-mg suppositories (Motilium®—Janssen Pharmaceutica). Pharmacokinetics The pharmacokinetics of domperidone have been studied after intravenous (2.5 mg/kg) and oral (2.5, 10, and 40 mg/kg) therapy in dogs. 35–37 Domperidone pharmacokinetics are described by a two-compartment model with a distribution half-life of 6 minutes and an elimination half-life of 2.45 hours.35–37 The bioavailability of domperidone is approximately 20%, and peak plasma levels are reached 120 minutes after oral administration. The drug is approximately 93% protein bound in the circulation, and the plasma clearance is 14.6 ml/min/kg. Domperidone is extensively metabolized and excreted as metabolites in the feces (66%) and urine (31%). The main metabolic pathways are aro-

matic hydroxylation and oxidative N-dealkylation. Domperidone has not been approved for use in the United States, and there is scant clinical experience with the drug in companion animals. Data from experimental studies suggest that a clinically effective dose would be 0.05 to 0.10 mg/kg administered orally once or twice per day.

Clinical Applications Lower Esophageal Sphincter Early reports suggested that domperidone increases lower esophageal sphincter pressure in healthy humans. 35 Subsequent reports, however, failed to demonstrate any effect of domperidone on lower esophageal sphincter pressure or on the amplitude or duration of esophageal contractions. 38 In dogs, domperidone induces phasic contractions of the lower esophageal sphincter but not the sustained increases in pressure that would be beneficial in treating gastroesophageal reflux. Furthermore, the phasic contractions are abolished by feeding.12 Domperidone thus may not be beneficial in treating gastroesophageal reflux disease in dogs or cats. Gastric Emptying As a prokinetic agent, domperidone is apparently most effective in improving clinical signs (e.g., anorexia and vomiting) associated with delayed gastric emptying. Studies in human patients with gastric emptying disorders have demonstrated efficacy of domperidone in stimulating gastric emptying of solids and liquids.35 Similar studies in dogs have yielded equivocal results. Preliminary reports suggested that domperidone improves gastric motility39 or antroduodenal coordination in dogs.40 A subsequent study demonstrated that domperidone actually decreases the frequency of corporeal, pyloric, and duodenal contractions and deteriorates antropyloroduodenal coordination by decreasing the frequency of contractions spreading from the antrum or pylorus to the duodenum.20 The latter study suggested that domperidone may not be very useful as a gastroprokinetic agent in dogs.20 The role of domperidone in gastroprokinetic treatment of dogs and cats thus remains to be defined. Small Intestine and Colon Domperidone has no effect on small intestinal motility. Colonic motility is also not affected by the agent.41 Emesis Domperidone is a potent antiemetic agent. It inhibits dopaminergic D2 receptor–mediated vomiting at the level of the chemoreceptor trigger zone.2,4,42 Vomiting

DOPAMINE–MEDIATED NEUROTRANSMISSION ■ TWO–COMPARTMENT MODEL

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induced by the chemoreceptor trigger zone stimulants (apomorphine and dopamine) thus is attenuated by domperidone infusion.2,42 Domperidone is 12 to 25 times more potent than metoclopramide and 50 to 60 times more potent than prochlorperazine in attenuating apomorphine-induced vomiting.2,43 Domperidone is less effective in attenuating neurally mediated emesis in dogs. Copper sulfate–induced vomiting, a centrally mediated phenomenon, is not affected by domperidone doses as high as 2.5 mg/kg.42 Vomiting induced by abdominal irradiation is also attenuated by domperidone in dogs44; however, the mechanism of the antiemetic effect is unclear because gastrointestinal and chemoreceptor trigger zone dopamine receptors are apparently not involved.44

Contraindications Domperidone should not be administered to animals treated with dopaminergic drugs. These drugs include dopamine and dobutamine. Pharmacologic Effects Gastrointestinal Effects Dopamine indirectly inhibits gastric smooth muscle contraction by activating presynaptic D2 dopaminergic and α2-adrenergic receptors on postganglionic cholinergic neurons7,8,45,46 (Figure 1). Dopamine also directly inhibits such contraction by activating postsynaptic β2adrenergic receptors on gastric smooth muscle cells.8 Domperidone antagonizes the indirect and direct inhibitory effects of dopamine, resulting in the stimulation of gastric smooth muscle contraction. It is not clear which pharmacologic effects (D2, α2, or β2) predominate in domperidone-induced contractions. Extragastrointestinal Effects The antiemetic effect of domperidone at the chemoreceptor trigger zone is apparently explained entirely by the inhibition of dopaminergic D 2 receptors.2,4,34 Domperidone also antagonizes central nervous system dopaminergic D3 and D4 receptors,47 but these effects may not be clinically relevant because domperidone does not readily cross the blood–brain barrier.34 Adverse Reactions Because domperidone has had limited use in veterinary medicine, very few adverse reactions have been reported in animals. Hyperprolactinemia, the most commonly reported adverse reaction in humans, is related to dopamine receptor antagonism at the median eminence of the adenohypophysis and in the tuberoinfundibular system.48 Somnolence and extrapyramidal reactions are rare

side effects associated with domperidone use in humans. Central nervous system side effects have been attributed to a compromised or developmentally immature blood–brain barrier.35 Several cases of cardiac arrhythmia, cardiac arrest, and sudden death have been associated with intravenous domperidone therapy. Because of documented cardiotoxicity, the parenteral form of the drug has been withdrawn by the manufacturer.35

Drug Interactions The oral absorption of domperidone is reduced by concomitant antacid or H2-receptor antagonist therapy.35 There is scant information concerning the effects of domperidone on the pharmacokinetics of other drugs.49

About the Authors Dr. Hall is affiliated with the College of Veterinary Medicine, Oregon State University, Corvallis, Oregon. Dr. Washabau is affiliated with the Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Drs. Hall and Washabau are Diplomates of the American College of Veterinary Internal Medicine.

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