DRUG PROFILE Tegaserod in the treatment of constipation-predominant functional gastrointestinal disorders Anurag Agrawal & Irritable bowel syndrome is a common condition for which, until recently, treatment Peter Whorwell† options have been limited. Tegaserod has selective serotonin subtype 4 receptor agonist †Author for correspondence activity and acts by increasing gastrointestinal motility, secretion and possibly reducing ERC Building, First Floor, Wythenshawe Hospital, visceral sensitivity. It has been developed to treat patients with irritable bowel syndrome Southmoor Road, who suffer from abdominal pain, constipation and bloating. Studies so far suggest that it is Manchester, M23 9LT, an effective treatment for these symptoms with an excellent safety profile. Its role in other UK Tel.: +44 161 291 5813 functional gastrointestinal disorders, such as functional dyspepsia, is still being assessed. Fax: +44 161 291 4184 This review describes the structure, pharmacokinetic and pharmacodynamic properties of tegaserod and its effect on gastrointestinal physiology, as well as its clinical utility. Irritable bowel syndrome (IBS) is the most com- drugs such as antidiarrheals, laxatives, antispas- mon condition dealt with by gastroenterolo- modics and antidepressants. Behavioral therapy gists, accounting for up to 30% of their practice is sometimes tried in patients who do not and 10% of primary care case loads [1]. It is respond to conventional treatment. characterized by abdominal pain or discomfort In addition to its costs to the patient, IBS also often related to a change in bowel habit and fre- has a significant direct and indirect economic quently exacerbated by eating. Investigation burden. The direct cost in terms of healthcare reveals no structural abnormality, although a utilization has been estimated to be between variety of gastrointestinal (GI) physiological US$1.7–10 billion/year in the USA alone. The changes have been described. Population-based indirect cost in terms of days off work and studies have suggested that the prevalence is impairment whilst at work can amount to between 10 and 15%, with some variation US$20 billion, with the common cold being the according to the population group studied or only condition that can match IBS in terms of its the diagnostic criteria used [2]. economic impact [4–6]. IBS can be classified as diarrhea-predominant Functional constipation is a very common (d-IBS), constipation-predominant (c-IBS) or condition that affects the general population. It alternating bowel habit (a-IBS) subtypes accord- is defined as a group of functional disorders that ing to the predominant bowel habit, with an present as persistent, difficult, infrequent or approximately equal prevalence between the seemingly incomplete defecation in the absence three groups. More recent studies have suggested of other features to suggest IBS (Rome II crite- that patients with alternating bowel habits tend ria). The estimates of the prevalence of constipa- to have a greater variation of their symptoms tion in North America range from 12 to 19% compared with the other subgroups, with this and up to 50% in patients above the age of 65 fluctuation tending to be greater between c-IBS years, with a female-to-male ratio of 2.2:1 [7]. In and a-IBS rather than c-IBS and d-IBS or d-IBS one cohort, 89% of patients with constipation and a-IBS. This has led to the suggestion that the still reported constipation at 14.7 months fol- term mixed IBS (m-IBS) should be used [3]. low-up. There is some evidence to suggest that The diagnosis of IBS is based on a clinical his- quality of life (QoL) is impaired in constipation; Keywords: bloating, tory and the absence of certain red flag features however, this is not conclusive [7,8]. constipation, irritable bowel such as rectal bleeding, weight loss, absence of syndrome, serotonin, family history of bowel cancer, inflammatory Treatment of IBS: unsatisfactory tegaserod bowel disease or celiac disease. Investigations solution to a common problem required to rule out other gastroenterological The ideal IBS treatment would provide rapid, conditions should generally be kept to a mini- sustained, global relief of the multiple symptoms mum and treatment includes a range of of IBS with a single, effective, well-tolerated Future Drugs Ltd approaches including dietary modification or agent. Treatments that target only single IBS 10.1586/14750708.3.4.475 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(4), 475–484 475 DRUG PROFILE – Agrawal & Whorwell symptoms are considered suboptimal forms of greatest trigger. Serotonin has a number of effects therapy by the Rome II Committee and the in the GI tract that are mediated by a variety of American College of Gastroenterology Func- receptor subtypes. Pancreatic and mucosal secre- tional Gastrointestinal Disorders Task Force tion as well as peristalsis are stimulated via the (ACG FGID) [9–11]. direct action of serotonin on enterocytes in addi- Although in some patients traditional IBS tion to its stimulatory effects on intrinsic primary treatment options are beneficial in relieving sin- afferent neurons. In addition to this effect, serot- gle symptoms (e.g., antispasmodics for abdomi- onin also activates extrinsic sensory nerves such as nal pain, laxatives for constipation, and the vagus and spinal nerves which innervate the antidiarrheal agents for diarrhea), none of these GI tract and thus has a role in the perception of drugs for IBS have been assessed in trials that ful- pain in the GI tract [13,14]. A recent study has sug- fill the recently introduced, rather strict criteria gested that IBS patients have reduced stores of set out by the European Committee for Medici- serotonin in the gut mucosa, which is independ- nal Products for Human use (CHMP). The ent of the bowel habit subtype, although EC cells CHMP recommended in 2003 that drugs which appear to be increased in the colonic mucosa of are used for short-term relief of IBS should be patients with post-infectious IBS [15,16]. There is assessed using a re-randomization design with evidence that circulating postprandial serotonin two primary outcome variables. Furthermore, levels vary between c- and d-IBS, with the former patient surveys demonstrate general dissatisfac- tending to be lower in healthy controls and the tion with most of the available agents and evi- latter higher [17]. These data, although somewhat dence-based support for their use is also lacking, conflicting, do suggest that disturbances in sero- with the ACG FGID Task Force claiming that tonergic function can lead to disturbance of GI the methodology in most clinical trials of these motility, sensation and secretion. older agents was flawed. They also concluded One of the key components of normal sero- that many studies only met the criteria for level 2 tonergic function is the rapid and effective clear- evidence (grade B recommendation), defined as ance of serotonin following release. The randomized, controlled trials with p > 0.05, less serotonin reuptake transporter (SERT) is a spe- than adequate sample sizes, poor methodology, cialized transporter protein that is responsible for or a combination of these flaws [12]. Although the the transcellular transport and intracellular bulking agents, antidiarrheals and tricyclic anti- deactivation of serotonin. SERT is inhibited depressants (TCAs) were found to relieve some therapeutically by selective serotonin reuptake of the single symptoms of IBS (constipation, inhibitors (SSRIs) and TCAs. Recent reports diarrhea and abdominal pain, respectively), these have identified differences in the genetic coding agents were not considered more effective than of IBS patients with diarrhea and constipation placebo in providing global relief of the multiple subtypes [18]. symptoms of IBS. In addition, these agents often There are at least seven different subclasses of cause adverse reactions, some of which may serotonin receptor, with at least 21 different mimic or exacerbate IBS symptoms (e.g., consti- subtypes. In the gut, serotonin receptors are pation from antidepressants and bloating from present mainly on gut neurons, smooth muscle high doses of fiber). cells and EC cells. Of the different receptor Over the last few years there has been a surge subtypes the most important are the 5-HT3 and of interest in a new class of drugs that modulate 5-HT4 subtypes. serotonin and its receptors, with the 5-HT3 There is a predominance of 5-HT3 receptors receptor antagonist alosetron and the 5-HT4 on the enteric neurons of the gut, where they receptor agonist tegaserod being the focus of have a variety of effects including the potential to much attention with respect to IBS therapy. control motility, fluid secretion and visceral sen- sitivity. Studies have also indicated that 5-HT4 Role of serotonin and its receptors in IBS receptors are located in the enteric neurons and Serotonin is distributed mainly in the enterochro- the smooth muscle with their stimulation lead- maffin (EC) cells, which are located in the epithe- ing to a prokinetic effect and enhanced fluid lium of the small intestine as well as the colon. secretion [13]. More recent work has indicated There are many triggers for serotonin release from that 5-HT4 receptors are present not only on EC cells, including mechanical distension, nutri- submucous and myenteric plexus neurons but ents, toxins, neurotransmitters and a change in also on the interstitial cells of Cajal, which may pH, with mechanical stimulation being the have a role in regulating motility [19]. 476 Therapy (2006) 3(4) Tegaserod – DRUG PROFILE Serotonin receptor modulators: The most extensively studied 5-HT4 agonists background are cisapride, prucalopride and tegaserod. Unfor- The serotonin receptors are among the most com- tunately, cisapride has the potential to provoke pelling targets for motility-modifying agents, ventricular arrhythmias and prolongation of the given the central role that serotonin plays in the QT interval and this is linked to HERG potas- initiation of the peristaltic reflex and the excita- sium channel blockade rather than 5-HT4 recep- tory action of serotonin on enteric neurons.