Safety and Tolerability of Tegaserod: PATHOPHYSIOLOGY
Brain-Gut Axis Dysfunction
Symptoms of IBS arise from three main physiological abnormalities: altered GI motility, altered intestinal secretion, and enhanced visceral sensitivity. Although the motor, secretory, and sensory activities of the gut are under the direct control of the enteric nervous system (ENS), the central nervous system (CNS) contributes indirectly by modulating the activities of the ENS through sympathetic and parasympathetic pathways. This bidirectional communication pathway is referred to as the brain-gut axis. The ENS controls intestinal motility and secretion and visceral sensation via neuro-transmitters such as serotonin (5-hydroxytryptamine [5-HT]), norepinephrine, dopamine, acetylcholine, and calcitonin generelated peptide (CGRP).
The neurotransmitter serotonin is produced and stored primarily in the gut mucosa. Indeed, almost 95% of the body’s 5-HT is made and stored in mucosal enterochromaffin (EC) cells in the GI tract. Serotonin plays a major role in communication between the ENS and its effector systems (Figure 1).
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Various 5-HT receptor subtypes exist in the body; those considered to have the largest role in GI regulation are 5HT1a, 5HT1P, 5-HT2, 5-HT3, and 5-HT4. Activation of the 5-HT3 receptors is associated with increased GI motility and secretion, whereas activation of the 5-HT4 receptors produces varied excitatory and inhibitory effects, including mediation of the relaxation and contraction of circular smooth muscle strips and induction of small-bowel and colonic fluid secre-tion. Serotonin initiates the peristaltic reflex that is mediated by the ENS. Results from in vitro studies from human, rat, and guinea pig intestines suggest that 5-HT4 receptors are its primary mediators.
Figure 1 The role of serotonin (5-hydroxytryptamine [5-HT]) in gastrointestinal regulation. CNS = central nervous system; ENS = enteric nervous system. (© Novartis Pharmaceuticals Corporation.)
The 5-HT receptor modulator tegaserod canadian was introduced to the U.S. market in July 2002 to treat women with IBS-C and was found to offer comprehensive relief of abdominal discomfort and constipation. Tegaserod is a highly selective 5-HT4 receptor partial agonist. It is a member of a novel class of compounds, the aminoguanidine indoles, and it is structurally similar to serotonin (Figure 2).
The development of tegaserod began with the structure of serotonin as a starting point, because serotonin is the natural ligand at 5-HT4 receptors. Tegaserod was then designed according to three principles—selectivity, stability, and polarity. To make tegaserod highly selective, scientists restricted the conformation of the alklyamine side chain. The primary amine was replaced by a basic moiety to give tegaserod greater stability against metabolic degradation. Finally, a relatively high molecular polarity was incorporated so that tegaserod would not cross the blood-brain barrier.
Tegaserod has 21% affinity for the 5-HT4 receptor, whereas endogenous 5-HT has 100% affinity. Partial agonists, in comparison with full agonists, are less likely to reduce receptor sensitivity and to produce tachyphylaxis (rapid immunization against the effect of toxic doses or a rapidly decreasing response to a drug after a few doses). A lower likelihood of 5-HT4 receptor desensitization is particularly relevant, because the G-protein-coupled, 7-transmembrane receptor class is especially prone to desensitization that leads to tachy-phylaxis or tolerance. Partial agonists may also have a normalizing effect on endogenous serotonin activity by increasing endogenous activity while decreasing the potential for the exaggerated effects sometimes associated with full agonists. cialis canadian pharmacy
Figure 2 Chemical structures of serotonin, tegaserod, and cisapride
Tegaserod stimulates the peristaltic reflex and intestinal secretion, and it inhibits visceral sensitivity by selectively binding to 5-HT4 receptors. It amplifies peristaltic reflexes without causing waves of nausea-evoking or pain-producing signals to be sent to the CNS because no 5-HT4 receptors are found on extrinsic sensory nerves. The probable presynaptic location of 5-HT4 receptors in the gut also enables tablet tegaserod to increase motility in response to endogenous mucosal stimulation without initiating constitutive, propulsive activity, which tends to cause painful, incapacitating diarrhea if it occurs.
