Elsevier

The Lancet

Volume 358, Issue 9298, 15 December 2001, Pages 2061-2068
The Lancet

New Drug Classes
Serotoninergic neuroenteric modulators

https://doi.org/10.1016/S0140-6736(01)07103-3Get rights and content

Summary

Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT3 receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT3 receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT4 receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT4 receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT4 agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined.

Section snippets

Pathophysiology of IBS

The concept that IBS is a neurological bowel disease is gaining ground, and the pejorative label “functional” may eventually be discarded. There is familial clustering and there may be a genetic predisposition.10 Food intolerance has been implicated in diarrhoea although its exact importance in IBS remains unclear.11

There is evidence that IBS can occur following infectious gastroenteritis and transient inflammation. For example, of patients admitted to hospital for bacterial gastroenteritis,

General management of IBS

Key management issues in IBS include a positive clinical diagnosis, tests to exclude other diseases, and, if required, targeting drug therapy for the major symptoms.2 Reassurance, explanation, advice about possible precipitating factors, and exploration of psychological issues may be therapeutic.2 Follow-up to determine the response to treatment and to reinforce these general principles also appears to be of value. A 30-year historical cohort study suggested that a good doctor-patient

Serotonin and IBS

Serotonin (5-hydroxytryptamine, 5HT) is a monoamine neurotransmitter of importance in brain-gut connection.25, 26 About 95% of the body's serotonin is present in the gut, 90% of it in the enterochromaffin cells and 10% in enteric neurons. Serotonin has complex actions; it can result in smooth-muscle contraction (via stimulation of cholinergic nerves) or relaxation (via stimulation of inhibitory nitric oxide releasing neurons).23 Mucosal release of serotonin stimulates both intrinsic sensory

5HT3 antagonists

5HT receptors are found on gut neurons and on smooth-muscle and enterochromaffin cells.23, 28, 29 There are seven families of 5HT receptor (and 21 or more subtypes, most of them in the central nervous system) but in the gut it is the 5HT3 and 5HT4 (and to a lesser extent 5HT1p, 5HT1a, and 5HT2) receptors that seem of most clinical relevance in terms of pharmacological manipulation.23, 30, 31

The 5HT3 receptor (M receptor), when stimulated, results in rapid depolarisation of myenteric neurons

Pharmacology

Alosetron is a highly selective central penetrating 5HT3 antagonist that is much more potent than ondansetron. For example, studies of isolated rat vagus nerve have shown that alosetron blocked serotonin-induced neuronal depolarisation with an estimated dissociation constant similar to that based on binding studies (0·2 nmol/L).26 In contrast, ondasetron failed to reduce the maximal serotonin response, suggesting that it binds less tightly to the 5HT3 receptors.26 Alosetron is rapidly absorbed

5HT4 agonists

5HT4 receptors are located on neurons in the myenteric plexus, and are found on primary afferent neurons, smooth-muscle cells, and enterochromaffin cells.58, 59, 60 These receptors mediate the localised release of neuro-transmitters in the colon in vitro, including acetylcholine, substance P, vasoactive intestinal peptide, and calcitonin-gene-related peptide that stimulate the peristaltic reflex61 (figure 2). However, as with the 5HT3 receptors, the effects are complex. 5HT4 receptors mediate

Pharmacology

Tegaserod, an aminoguanidine indole similar to serotonin (figure 1), is a partial 5HT4 receptor agonist with high potency and specificity. Tegaserod is rapidly absorbed and has a half-life of 11 h (panel 2).67, 68 There appears to be a biphasic dose-response relationship.69 Tegaserod is metabolised to an inactive glucuronide conjugate in the small bowel and liver; two-thirds is excreted unchanged in stool (which theoretically could have a topical action) and one-third by the kidneys. In

Pharmacology

Prucalopride, a benzofurancarboxamide (figure 1), is a selective and potent 5HT4 receptor agonist that has been tested in idiopathic chronic constipation.75, 76 Normally, high-amplitude propagated colonic contractions occur a few times daily, especially on wakening or after a meal, and often an urge to defecate follows.77 Prucalopride induces high propagated amplitude contractions in the colon in a dose-dependent manner in laboratory animals, and in a dose-dependent manner accelerated proximal

Other serotoninergic drugs in development

Drug combinations of serotoninergic agents (eg, tegaserod plus cilansetron) have not been formally tested in IBS. Whether a 5HT3 antagonist and 5HT4 agonist could be usefully used together is unknown.

5HT4 antagonists theoretically may be antidiarrhoeal and antinociceptive;23 two compounds under evaluation are sulamserod and piboserod. However, a role in diarrhoea-predominant IBS has not been documented. In health, the 5HT4 antagonist SB-207266 in doses that antagonised the effects of the 5HT4

Drugs other than serotoninergic modulators

The new serotoninergic agents need to be put into the perspective of other drugs available for IBS. Unfortunately, direct comparisons remain difficult because outcome measures have been different, trial methods have been suboptimal, and hardly any head-to-head comparisons have been done.24

Alternatives for diarrhoea-predominant IBS include the opioid agonists diphenoxylate and loperamide, which slow gastrointestinal transit via effects on circular and longitudinal muscle as well as increasing

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