Review article: new receptor targets for medical therapy in irritable bowel syndrome

Abstract

Background: Despite setbacks to the approval of new medications for the treatment of irritable bowel syndrome, interim guidelines on endpoints for irritable bowel syndrome (IBS) trials have enhanced interest as new targets for medical therapy are proposed based on novel mechanisms or chemical entities.

Aims: To review the approved lubiprostone, two targets that are not meeting expectations (tachykinins and corticotrophin-releasing hormone), the efficacy and safety of new 5-HT(4) agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase-C agonists), bile acid modulation, anti-inflammatory agents and visceral analgesics.

Methods: Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics and efficacy.

Results: The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS and these effects are associated with pain relief. The pivotal mechanisms responsible for the abdominal pain or visceral sensation in IBS are unknown. The new 5-HT(4) agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability and high efficacy. The potential risks of agents 'borrowed' from other indications (such as hyperlipidaemia, inflammatory bowel disease or somatic pain) deserve further study.

Conclusions: There is reason for optimism in medical treatment of IBS with a spectrum of agents to treat bowel dysfunction. However, visceral analgesic treatments are still suboptimal.

Figure 1

Chloride transport is also pivotal in the regulation of fluid secretion in the gastrointestinal tract by organs that drain into the intestine. This model of the chloride secretory mechanism in intestinal epithelial cells shows that secretion can be stimulated by increases in intracellular messengers, either cyclic nucleotides (cAMP/cGMP) or cytosolic calcium ([Ca2`]i). Major targets for regulation of secretion include channels in the apical membrane: CFTR, cystic fibrosis transmembrane conductance regulator; CaCC, calcium-activated chloride channel and ClC-2 (chloride channel type 2). Activation of these channels by the intracellular messengers is indicated with solid arrows, with additional postulated sites of action indicated with broken arrows. The identity of basolateral potassium channel(s) involved in either cyclic nucleotide- or calcium-mediated chloride secretion is unknown. Ion channels in the basolateral membrane serve to deliver chloride into the enterocytes, while ensuring that the obligatorily co-transported cations are extruded by energy-dependent (e.g. ATP) mechanisms. These transporters are particularly needed to re-cycle potassium ions. They include: NKCC1 (sodium/potassium/2 chloride co-transporter type 1), IK, intermediate conductance potassium channel; K-cAMP channel, putative potassium channel regulated by cAMP and KCNQ1/KCNE3 heteromeric K+ channels (not shown). Adapted from ref. , Barrett KE, Keely SJ. Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu Rev Physiol 2000;62:535-72.