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Clinical implications of enteric and central D 2 receptor blockade by antidopaminergic gastrointestinal prokinetics
Author(s) -
Tonini M.,
Cipollina L.,
Poluzzi E.,
Crema F.,
Corazza G. R.,
De Ponti F.
Publication year - 2004
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/j.1365-2036.2004.01867.x
Subject(s) - medicine , domperidone , pharmacology , area postrema , receptor , metoclopramide , endocrinology , dopamine , vomiting
Summary 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 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 blood–brain 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.