Drugs stimulating gastrointestinal motility Domina Petric, MD

Prokinetic agents are drugs that selectively stimulate gut motor function. Agents that increase lower esophageal sphincter pressures may be useful for GERD. Drugs that improve gastric emptying may be helpful for gastroparesis and postsurgical gastric emptying delay. Agents that stimulate the small intestine may be useful for postoperative ileus or chronic intestinal pseudo-obstruction. Agents that enhance colonic transit: for constipation. Introduction

Physiology of the enteric nervous system

The enteric nervous system The enteric nervous system is composed of interconnected networks of ganglion cells and nerve fibers mainly located in the submucosa (submucosal plexus) and between the circular and longitudinal muscle layers (myenteric plexus). The enteric nervous system

The enteric nervous system Mucosa Epithelium Lamina propria Muscularis mucosa Submucosa Meissner´s (submucosal) plexus Muscularis propria Circular muscle Auerbach´s (myenteric) plexus Longitudinal muscle Serosa/adventitia The enteric nervous system

The enteric nervous system These plexuses give rise to nerve fibers that connect with the mucosa and muscle. Extrinsic sympathetic and parasympathetic nerves project onto the submucosal and myenteric plexuses. The enteric nervous system can independently regulate gastrointestinal motility and secretion. The enteric nervous system

The enteric nervous system Extrinsic primary afferent neurons project via the dorsal root ganglia or vagus nerve to the central nervous system. Release of serotonin (5-HT) from intestinal mucosa enterochromaffin (EC) cells stimulates 5-HT3 receptors on the extrinsic afferent nerves. Serotonin is stimulating nausea, vomiting and abdominal pain. The enteric nervous system

The enteric nervous system Serotonin also stimulates submucosal 5-HT1P receptors of the intrinsic primary afferent nerves (IPANs). IPANs contain calcitonin gene-related peptide (CGRP) and acetylcholine. IPANs project to myenteric plexus interneurons. 5-HT4 receptors on the presynaptic terminals of the IPANs appear to enhance release of CGRP or acetylcholine. The enteric nervous system

The enteric nervous system The myenteric interneurons are important in controlling the peristaltic reflex, promoting release of excitatory mediators proximally and inhibitory mediators distally. Motilin may stimulate excitatory neurons or muscle cells directly. Dopamine acts as an inhibitory neurotransmitter in the gastrointestinal tract, decreasing the intensity of esophageal and gastric contractions. The enteric nervous system

Cholinomimetic agents II.

Cholinomimetic agonists, like bethanechol, stimulate muscarinic M3 receptors on muscle cells and at myenteric plexus synapses. Bethanechol is now seldom used. The acetylcholinesterase inhibitor neostigmine can enhance gastric, small intestine and colonic emptying. Cholinomimetics

Intravenous neostigmine is sometimes used for the treatment of hospitalized patients with acute large bowel distention: colonic pseudo-obstruction (Ogilvie´s syndrome). Administration of 2 mg iv. results in prompt colonic evacuation of flatus and feces in the majority of patients. Cholinergic effects are excessive salivation, nausea, vomiting, diarrhea and bradycardia. Cholinomimetics

Ogilvie˙s syndrome Source: Wikipedia.org

Metoclopramide, domperidone III.

Metoclopramide and domperidone are dopamine D2 receptor antagonists. Activation of dopamine receptors within the gastrointestinal tract inhibits cholinergic smooth muscle stimulation. Blockade of dopamine has prokinetic effect. Dopamine antagonists

Dopamine antagonists These agents: increase esophageal peristaltic amplitude increase lower esophageal sphincter pressure enhance gastric emptying have no effect on small intestine and colonic motility Dopamine antagonists

Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action. Dopamine antagonists

Metoclopramide and domperidone are sometimes used in the treatment of symptomatic GERD, but are not effective in patients with erosive esophagitis. Prokinetic agents are used mainly in combination with antisecretory agents in patients with regurgitation or refractory heartburn. Clinical use

These agents are used in the treatment of patients with delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis. Metoclopramide is sometimes administered in hospitalized patients to promote advancement of nasoenteric feeding tubes from the stomach into the duodenum. Clinical use

These agents lead to symptomatic improvement in a small number of patients with chronic dyspepsia. Metoclopramide and domperidone are used for the prevention and treatment of emesis because of their potent antiemetic action. Domperidone is sometimes recommended to promote postpartum lactation. Clinical use

Adverse effects, metoclopramide The most common adverse effects of metoclopramide involve the central nervous system. Restlessness, drowsiness, insomnia, anxiety and agitation (10-20% of patients, especially elderly). Adverse effects, metoclopramide

Adverse effects, metoclopramide Extrapyramidal effects are dystonias, akathisia and parkinsonian features. Extrapyramidal effects are due to central dopamine receptor blockade. Occur acutely in 25% of patients given high doses and in 5% of patients receiving long-term therapy. Adverse effects, metoclopramide

Adverse effects, metoclopramide Tardive dyskinesia, sometimes irreversible, has developed in patients treated for a prolonged period with metoclopramide. Long-term use should be avoided unless absolutely necessary. Elevated prolactin levels (both with metoclopramide and domperidone) can cause galactorhea, gynecomastia, impotence and menstrual disorders. Adverse effects, metoclopramide

Adverse effects, domperidone Domperidone is well tolerated. It does not cross the blood-brain barrier to a significant degree. Neuropsychiatric and extrapyramidal effects are rare. Adverse effects, domperidone

Macrolides IV.

Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote the onset of a migrating motor complex. Iv. erythromycin 3 mg/kg is beneficial in some patients with gastroparesis, but tolerance develops rapidly. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood before endoscopy. Macrolides

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology. Wikipedia.org Literature