Rational pharmacotherapy of gastrointestinal motility disorders

Abstract

Nervous control of gastrointestinal motility is extremely complex, is regulated by the enteric system, the "brain of the gut", and modulated by extrinsic nerves. This system with its multiplicity of transmitters and receptors does not always allow a clear interpretation of experimental data, especially with compounds lacking specificity. In this review the complex situation is described particularly in relation to receptor populations (cholinergic, adrenergic, dopamine, histamine, 5-hydroxytryptamine, opioid, gamma-aminobutyric acid (GABA), prostanoid and dihydropyridine receptors), therapeutic aspects of drugs and their usefulness in children. Newer principles with known drugs and promising new compounds with a more appropriate kinetic or fewer side-effects, deriving from distinct pharmacological groups, as candidates for the treatment of gastrointestinal disorders are considered e.g. anticholinergics (prifinium or actilonium bromide), adrenergic alpha 2-agonists (clonidine, lidamidine) for diarrhoea in diabetic neuropathy, adrenergic beta-blockers for shortening postoperative ileus (propranolol), dopamine receptor antagonists (metoclopramide, domperidone, alizapride) and another prokinetic substance (cisapride) which may be useful for a number of applications as gastro-oesophageal reflux, gastro-paresis, intestinal pseudo-obstruction, cystic fibrosis and constipation, morphine derivatives (e.g. loperamide) for intractable diarrhoea and calcium antagonists (e.g. nifedipine) for achalasia. Increasing experience in digestive tract pharmacology and reliable clinical studies will furthermore be the basis for a more specific and better tolerated therapy of gastrointestinal motility disorders in adults and children.

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

“…23 It is likely that the blockade of these inhibitory receptors by selective antagonists results in a gastroprokinetic effect ( Figure 1). Other mechanisms, however, have been claimed to explain the prokinetic effect of compounds such as domperidone and clebopride.…”

Promotility Medications – Now and in the Future

“…Dopamine reduces lower esophageal sphincter (LES) tone, reduces gastric tone and impairs antroduodenal coordination [1][2][3] . These effects are partly due to activation of D 2 dopamine receptors and the blockade of these inhibitory receptors by selective antagonists, such as domperidone and metoclopramide, have been suggested to result in a prokinetic effect [3][4][5] .…”

Gastrointestinal Receptors and Drugs in Motility Disorders

“…Although metoclopramide and domperidone seem to have similar efficacy as cisapride, this com pound was generally better tolerated, and serious adverse reactions did not occur as shown in most studies. Particularly because of its lack of antidopaminergic effects, its use may be of interest in children [3], Summarizing all these studies with cisa pride. more and longer comparisons with active drugs are necessary to assess the ther apeutic progress which is claimed for this compound.…”

“…Two subtypes of adrenergic a-(ct|, a2) and p-(Pi< P2) receptors are known and have been recognized also in the gastrointestinal tract [3,26,27], a/ Adrenoceptors. Most adrenergic fibers end in the region of the intramural ganglia or on blood vessels and only few penetrate to the peripheral effector cells.…”

“…Risks and precautions of opioid therapy in this group of patients have been evaluated [3]. Studies in adults have been done with patients suffering from Crohn's disease and ulcerative colitis [104,105], IBS [106.…”