Antidopaminergic 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 D2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D2 receptors, ability to interact with other receptor systems [
5-hydroxytryptamine-3 (5-HT3) and 5-HT4 receptors for
metoclopramide; 5-HT4 receptors for
levosulpiride) and ability to permeate the blood-brain barrier (compared with the other compounds,
domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5-HT4) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in
gastrointestinal disorders, such as functional
dyspepsia and diabetic
gastroparesis. The antagonism of central D2 receptors may lead to both therapeutic (e.g.
anti-emetic effect due to D2 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 D2 receptor (i.e. compounds that bind loosely to D2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D2 receptor pharmacology can help the clinician to choose between the antidopaminergic prokinetics to obtain a more favourable risk/benefit ratio.