What Are the Emerging Therapeutic Agents for Constipation and How Do They Modulate Colonic Motility?
The enteric nervous system (ENS) contains as many neurons as the spinal cord, which are spatially distributed along the digestive tract in close proximity to effector organs (smooth muscle, glandular epithelium), allowing for rapid, automatic feedback control. Interneurons and motor neurons are interconnected by chemical synapses to comprise functional neural networks that receive synaptic input from sensory neurons that detect changes in the thermal, chemical, or mechanical local environment.1 Understanding the functional basis of the ENS, especially with respect to motility and secretion, is crucial for achieving a better understanding of how to manage patients with chronic constipation (Figure 19-1).
Figure 19-1. The integration of the enteric nervous system with the central nervous system and gastrointestinal tract. Adapted from Wood J. Neuropathophysiology of functional gastrointestinal disorders. World J Gastroenterol. 2007;13(9):1313-1332; and Gershon MD. Review article: serotonin receptors and transporters—roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther. 2004;20 Suppl 7:3-14.
Motor neurons in the ENS fall into 2 broad categories: excitatory or inhibitory. Excitatory motor neurons promote contraction of the gastrointestinal tract smooth muscle and secretion from mucosal glands. The primary excitatory neurotransmitters involved in muscle contraction include acetylcholine and substance P. Inhibitory motor neurons release neurotransmitters that suppress contractile activity and secretion. These include vasoactive intestinal polypeptide, nitric oxide, and Adenosine-5’-triphosphate.1,2 Gastrointestinal contractions may be classified on the basis of their duration. Short duration contractions are known as phasic contractions and sustained contractions are called tonic contractions. Tonic contractions play a primary role in organs with reservoir functions (stomach, colon) and sphincter function, whereas phasic contractions are critical for the mixing of gastrointestinal contents and propulsion of those contents in an aboral direction. Colonic motility patterns are also classified as segmental activity or propagated activity. Segmental activity consists of single bursts of arrhythmic, low amplitude contractions that create a pressure gradient that slowly pushes intestinal contents toward the rectum. Propagated activity occurs in the form of low amplitude propagated contractions (LAPC) or high amplitude propagated contractions (HAPC). LAPCs occur more than 100 times per day and are important for the transport of fluid within the colon.3 HAPCs occur about 6 times per day and are the prototypical stripping waves that are involved in mass movements of fecal contents large distances within the colon. HAPCs are considered one of the driving forces behind defecation.3 Dysfunctional gastrointestinal motility may arise through alterations of the control mechanisms at any level of the gut through to the central nervous system.
Secretion in the gastrointestinal tract is primarily mediated by secretomotor neurons that are located in the submucosal plexus of the ENS. They receive input from other ENS neurons (intrinsic nerves), as well as from sympathetic postganglionic nerves. Local paracrine messengers from non-neural cells such as enterochromaffin cells, mast cells, and other inflammatory cells can have a profound influence on the excitability of these secretomotor neurons. Excitatory input to secretomotor neurons is mediated by acetylcholine, vasoactive intestinal polypeptide, substance P, and serotonin. When stimulated, these neurons release acetylcholine and vasoactive intestinal polypeptide at both submucosal arterioles and intestinal glands. At the arterioles, acetylcholine promotes the release of nitric oxide to cause vasodilatation and at the intestinal crypt cells, Brunner’s glands, and goblet cells, acetylcholine directly promotes the release of H2O, NaCl, bicarbonate, and mucus into the intestinal lumen through specific channels as well as via passive diffusion. Inhibitory inputs include somatostatin-mediated messages from intrinsic ENS nerves and norepinephrine-mediated messages from postganglionic sympathetic nerves. Clinical examples of elevated secretomotor neuron activity include inflammatory bowel disease, in which inflammatory mediators excite the secretomotor neurons to release neurotransmitters and increase secretion, manifesting as diarrhea. Neuropathic conditions that diminish the functional or structural integrity of the ENS may be associated with diminished secretomotor neuron activity and may manifest as constipation.
Chloride and bicarbonate secretion provides 5 major physiologic functions in the digestive tract, including: 1) provision of an aqueous phase for digestion and absorption of meals, 2) hydration of mucus, 3) facilitation of the delivery of antibodies and cryptins (antimicrobial ligands) into the gut lumen, 4) helping to purge intestinal pathogens and noxious agents, and 5) adjusting luminal pH to optimize nutrient digestion and absorption.4 Transporters that enable chloride secretion are located on the basolateral side of enterocytes. When chloride channels in the luminal or apical membrane open, active chloride secretion occurs, followed by passive diffusion of sodium and water. One of these channels is the cystic fibrosis transmembrane regulator (CFTR), which is highly regulated by second messengers. A second chloride transporter, the type 2 chloride channel (ClC-2), is also present in the luminal membrane. Therapeutic agents that can affect these channels have the potential to increase chloride and fluid secretion into the lumen and thus have therapeutic implications for patients with constipation.
Agents That Target GI Receptors in Constipation
Tegaserod, a partial 5-hydroxytryptamine (HT)4 receptor agonist, is approved in the United States for the treatment of irritable bowel syndrome with constipation (IBS-C) in women, and chronic constipation in men and women younger than 65 years. Tegaserod accelerates transit by stimulating 5-HT4 receptors in the ENS, thus increasing the release of proximal stimulatory and distal inhibitory neurotransmitters in the ENS, which in turn augments peristalsis. Tegaserod has been shown to improve the symptoms of constipation, bloating, and straining compared with placebo.5 However, in March 2007, the manufacturer suspended marketing and sales of tegaserod because review of clinical trial data found that patients randomized to tegaserod had a higher risk of myocardial infarction, stroke, and unstable angina (heart/chest pain) compared with placebo. In April 2008, access to tegaserod was further restricted to emergency situations (defined as those that are immediately life-threatening or serious enough to warrant hospitalization).
Several mixed 5-HT4 receptor agonists/5-HT3 receptor antagonists are currently undergoing evaluation for the treatment of patients with symptomatic constipation. Camilleri and colleagues recently presented the combined results from 3 randomized double-blind trials showing that prucalopride was safe and effective at doses of 2 mg or 4 mg per day in patients with chronic idiopathic constipation.6 For the 3 trials combined, 23.6% of patients in the 2-mg group and 24.7% of patients in the 4-mg group, compared with 11.3% in the placebo group, had an average of >3 spontaneous complete bowel movements per week over the 12-week treatment period (P<.001 for both dosage comparisons). Prucalopride has also demonstrated significant improvement over placebo in a phase 2, double-blind, placebo-controlled trial involving 180 patients with opioid-induced constipation.7
There are 5 different types of opiate receptors that have been found to modulate gut motor and sensory functions. Among these, mu receptor-avid agents have demonstrated the most promise as possible therapies for chronic constipation, specifically for patients with opioid-induced constipation. Alvimopan is a peripherally acting mu-opioid receptor antagonist that has been shown to selectively block the peripheral effects of morphine without appreciably decreasing its centrally-mediated analgesic effects and is currently FDA approved for the treatment of postoperative bowel dysfunction. It has been shown to accelerate colonic transit in healthy volunteers not taking opiates, and several phase 3 studies have demonstrated a clinically significant promotility effect of alvimopan in patients with postoperative ileus.8,9 Another mu receptor antagonist, methylnaltrexone, is approved for the treatment of opioid-induced constipation. It is derived from the methylation of naltrexone, resulting in a molecule that does not readily cross the blood-brain barrier. A recently published phase 3 trial with methylnaltrexone in opioid-using patients with advanced illnesses showed that patients randomized to methylnaltrexone were 33% more likely to have defecation within 4 hours after at least 1 dose of methylnaltrexone.10 An open-label extension study confirmed the persistence of the response and the absence of narcotic withdrawal symptoms.
Lubiprostone is a bicyclic fatty acid that selectively activates intestinal type-2 chloride channels on the apical intestinal membrane, thus increasing fluid secretion into the intestinal lumen. It is currently the only fully available prescription medication indicated for the treatment of chronic idiopathic constipation in the adult population. In clinical trials of lubiprostone, patients who received 24 mcg twice daily experienced significantly more spontaneous bowel movements than patients who received placebo (P<.002 at all weeks).11,12 The most common side effect with this agent is nausea, which can be minimized when patients take lubiprostone with fluid and food.
Linaclotide is a potent guanylate cyclase-C agonist that acts peripherally to increase the production of cyclic guanosine monophosphate in human colon cells, leading to eventual activation of the CFTR to increase chloride, bicarbonate, and water secretion into the colon. Lembo recently presented the results of a phase 2b study involving 207 patients with chronic constipation who received 4 different doses of linaclotide over a 4-week period.13 The intent-to-treat analysis showed that at doses greater than 75 mcg, patients experienced statistically significant improvements in complete spontaneous bowel movement frequency, as well as improvements in stool consistency, straining, bloating, and abdominal discomfort. The most common adverse event was diarrhea, which resulted in discontinuation in 3% of linaclotide-treated patients.
1. Wood J. Neuropathophysiology of functional gastrointestinal disorders. World J Gastroenterol. 2007;13(9):1313-1332.
2. Gershon MD. Review article: serotonin receptors and transporters—roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther. 2004;20 suppl 7:3-14.
3. Bassotti G, de Roberto G, Castellani D, Sediari L, Morelli A. Normal aspects of colorectal motility and abnormalities in slow transit constipation. World J Gastroenterol. 2005;11(18):2691-2696.
4. Harrell LE, Chang EB. Intestinal water and electrolyte transport. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. 8th ed. Philadelphia, PA: Saunders; 2006:2127-2146.
5. Quigley EM, Wald A, Fidelholtz J, Boivin M, Pecher E, Earnest D. Safety and tolerability of tegaserod in patients with chronic constipation: pooled data from two phase III studies. Clin Gastroenterol Hepatol. 2006;49(5):605-613.
6. Camilleri M, Gryp RS, Kerstens R, et al. Efficacy of 12-week treatment with prucalopride (Resolor®) in patients with chronic constipation: combined results of three identical, randomized, double-blind, placebo-controlled phase 3 trials. Gastroenterology. 2008:134:suppl 1:A-548.
7. Moulin DE, Rykx A, Kerstens R, et al. Randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety of prucalopride (Resolor®) in patients with opioid induced constipation. Gastroenterology. 2008:134:suppl 1 A-642.
8. Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study. Surg Endosc. 2006;20(1):64-70.
9. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48(6):1114-1125.
10. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332-2343.
11. Johanson JF, Gargano MA, Holland PC, et al. Initial and sustained effects of lubiprostone, a chloride channel-2 (CIC-2) activator for the treatment of constipation: data from a 4-week phase III study [abstract]. Am J Gastroenterol. 2005;100:S324–S325.
12. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol. 2008;103(1):170-177.
13. Lembo A. Linaclotide significantly improved bowel habits and relieved abdominal symptoms in adults with chronic constipation: data from a large four-week, randomized, double-blind, placebo-controlled study. Gastroenterology. 2008:134:suppl 1:P-100.