Indirectly acting cholinomimetic agents - Increase of release
The principal drug which acts by releasing acetylcholine is cisapride.
Cisapride induces acetylcholine release by cholinergic fibers of the digestive tract, which increases motricity of the esophagus, stomach, duodenum, small intestine and colon. It increases, moreover, the pressure of the lower sphincter of the esophagus, thus opposing gastroesophageal reflux. Contrary to metoclopramide, cisapride does not have an antidopamine effect but it has an agonist effect on serotonin 5HT4 receptors, which reinforces its prokinetic effect.
The essential therapeutic indication of cisapride is gastroesophageal reflux. It is, of course, contraindicated if there is an organic obstacle to the progression of the bolus. It can give intestinal pains, diarrhea, and modify the kinetics of absorption of other drugs.
Atropine prevents the effects of cisapride by inhibiting muscarinic receptors.
Cisapride does not have central action because, in usual conditions, it does not cross the blood-brain barrier.
Catabolism of cisapride by the P-450 cytochrome can be inhibited by the concomitant intake of other drugs such as ketoconazole, miconazole, itraconazole and macrolides. This type of interaction, induces an increase of cisapride concentration , which can lead to the lengthening of QT electrocardiogram space by slowing repolarization and risk of torsades de pointes, in particular in case of hypokalemia and hypomagnesemia.
This risk of cardiac conduction disorders, sometimes fatal, led to the discontinuation of cisapride marketing in many countries and to restrictions of its prescription in other countries where reinforced warnings were introduced into the SPC of cisapride; they mention in particular the risk of interactions with many other drugs.
Notice
Botulinum toxin and the tetanic toxin are zinc proteins which have an opposite effect to that of cisapride, they inhibit the acetylcholine release by inactivating its transport proteins.
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