Clinical implications of enteric and central D₂ receptor blockade by antidopaminergic gastrointestinal prokinetics

Abstract

SUMMARYAntidopaminergic gastrointestinal prokinetics (bromopride, clebopride, domperidone, levosulpiride and metoclopramide) have been exploited clinically for the management of motor disorders of the upper gastrointestinal tract, including functional dyspepsia, gastric stasis of various origins and emesis. The prokinetic effect of these drugs is mediated through the blockade of enteric (neuronal and muscular) inhibitory D 2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D 2 receptors, ability to interact with other receptor systems [5-hydroxytryptamine-3 (5-HT 3 ) and 5-HT 4 receptors for metoclopramide; 5-HT 4 receptors for levosulpiride) and ability to permeate the bloodbrain barrier (compared with the other compounds, domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5-HT 4 ) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in gastrointestinal disorders, such as functional dyspepsia and diabetic gastroparesis. The antagonism of central D 2 receptors may lead to both therapeutic (e.g. anti-emetic effect due to D 2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. As the pituitary (as well as the area postrema) is outside the blood-brain barrier, hyperprolactinaemia is a side-effect occurring with all antidopaminergic prokinetics, although to different extents. Extrapyramidal reactions are most commonly observed with compounds crossing the blood-brain barrier, although with some differences amongst the various agents. Prokinetics with a high dissociation constant compared with that of dopamine at the D 2 receptor (i.e. compounds that bind loosely to D 2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D 2 receptor pharmacology can help the clinician to choose between the antidopaminergic prokinetics to obtain a more favourable risk/ benefit ratio.

Physiological Modulation of Intestinal Motility by Enteric Dopaminergic Neurons and the D2Receptor: Analysis of Dopamine Receptor Expression, Location, Development, and Function in Wild-Type and Knock-Out Mice

“…5-HT 4 receptors, moreover, like D 2 , are most concentrated on neurites within enteric ganglia (Liu et al, 2005). Domperidone (Barone, 1999;Drolet et al, 2000) and tegaserod are both used therapeutically as prokinetic agents, although domperidone is often thought to be more effective on the proximal gut (Longo and Vernava, 1993;Jost, 1997) and so has been used to relieve the symptoms of dyspepsia and gastroparesis (Horowitz and Fraser, 1995;Tonini et al, 2004), whereas tegaserod is used to treat chronic constipation and constipation-predominant irritable bowel syndrome (Prather et al, 2000;Muller-Lissner et al, 2001;Johanson, 2004;Galligan and Vanner, 2005). Domperidone and DA, however, have both been shown to exert effects on the colon and rectum as well as on the upper bowel (Wiley and Owyang, 1987), whereas tegaserod accelerates gastric emptying (Degen et al, 2001;James et al, 2004;Crowell et al, 2005) and has also been useful in treating dyspepsia and gastroparesis (Banh et al, 2005;Galligan and Vanner, 2005;Zuberi et al, 2005).…”

Functional and neurochemical changes of the gastrointestinal tract in a rodent model of Parkinson's disease

“…The inhibitory effect of dopamine is exerted through activation of prejunctional D 2 receptors located on cholinergic neurons leading to delayed gastric emptying. Indeed, in patients with PD, peripheral dopamine D 2 antagonist domperidone improves gastric emptying delayed by L-DOPA treatment [29].…”

Prokinetics in the Management of Functional Gastrointestinal Disorders

“…Domperidone, a dopamine antagonist that does not cross the blood-brain barrier and operates primarily through peripheral (DA 2 ) receptors, is available for use throughout Europe, as well as in Canada, Mexico, and South America but not in the United States. 9,10 The efficacy of metoclopramide in motility disorders has been far from consistent, and its long-term use has been complicated by a trend toward tolerance and a significant incidence of CNS side effects. 11 Up to 25% of patients may experience side effects, the most troubling of which are extrapyramidal reactions.…”