1 / 25

5-HT 4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod

5. 5-HT 4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod. Michael Camilleri, MD Gastroenterology Research Unit Mayo Clinic Foundation. 5. 5-HT 4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod.

stacy
Download Presentation

5-HT 4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 5 5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod Michael Camilleri, MD Gastroenterology Research UnitMayo Clinic Foundation

  2. 5 5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod • Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions • Tegaserod, a partial 5-HT4 receptor agonist, and its pharmacodynamic effects on the GI tract

  3. 5 OH NH2 NH Physiologic Distribution of Serotonin(5-Hydroxytryptamine, 5-HT) 5% CNS 5-Hydroxytryptamine • 95% GI tract • 90% ECs • 10% Neurons

  4. 5 Role of 5-HT in the GI Tract • Four main 5-HT receptor subtypes identified in the human GI tract : 5-HT1, 5-HT2, 5-HT3, and 5-HT4 • Diverse effects due to different receptor subtypes • 5-HT3 and 5-HT4 receptors involved in multiple GI functions: motor, sensory, secretory • Location of 5-HT4 receptors: neurons, EC cells, enterocytes, smooth muscle cells

  5. 5 MOA 5 Intrinsic Signaling Pathways Dorsal Root Ganglion CNS Serosa Longitudinal muscle Inhibition Myenteric plexus Excitatorymotor neuron Inhibitorymotor neuron Circular muscle Intrinsic primary afferent neurons Extrinsic primary afferent neurons Activation Submucosal plexus Muscularis mucosae Lamina propria Epithelium 5-HT ECs Enterocytes ECs ECs: Enterochromaffin cells 5-HT4 receptor

  6. 5 MOA 6 Extrinsic Signaling Pathways Dorsal Root Ganglion CNS Inhibition Serosa Longitudinal muscle Myenteric plexus Excitatory motor neuron Inhibitory motor neuron Circular muscle Extrinsic primary afferent neurons Intrinsic primary afferent neurons Submucosal plexus Muscularis mucosae Lamina propria Epithelium ECs Enterocytes ECs ECs: Enterochromaffin cells 5-HT4 receptor

  7. 5 5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod • Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions • Tegaserod, a partial 5-HT4 receptor agonist, and its pharmacodynamic effects • Effects on motility • Effects on visceral sensitivity

  8. 5 Tegaserod A representative of a new chemical class of compounds, aminoguanidine indoles, designed to act specifically at 5­HT4 receptors in the GI tract: OH O NH Serotonin NH NH NH2 N Tegaserod NH NH

  9. 5 Pharmacologic Profile of Tegaserod • Tegaserod, a partial agonist, displays high affinity for human 5-HT4 receptors (KB = 18 nM) • Tegaserod mimics action of 5-HT and potently stimulates intrinsic sensory neurons triggering the peristaltic reflex (EC50 5 nM) • Tegaserod has negligible affinity for 5-HT3 receptors (KB = 7,200 nM); therefore, it is devoid of relevant 5-HT3 receptor antagonism

  10. 5 Tegaserod Triggers the Peristaltic Reflex ACh, Substance P VIP, PACAP, NO activation 5-HT Tegaserod Enterocytes ECs

  11. 5 Tegaserod alone + 5-HT3 antagonist + 5-HT4 antagonist Neurotransmitter Release Induced by Tegaserod is Inhibited by Selective 5-HT4 Antagonist VIP Substance P 8 8 7 7 6 6 5 5  fmol / 100 mg · min  fmol / 100 mg · min 4 4 3 3 2 2 1 1 0 0 Human jejunum Guinea pig colon Rat colon Human jejunum Guinea pig colon Rat colon Means ± SE (n = 3 - 8) Grider et al. Gastroenterology 1998; 115: 370-380

  12. 5 Tegaserod-Induced Propulsion in Guinea Pig Colon Velocity of propulsion 200 180 160 140 % of control 120 100 80 0 1 10 100 1,000 Tegaserod concentration (nM) Means ± SEM (n = 3 - 4) Jin et al. J. Pharmacol. Exp. Ther. 1999; 288: 93-97

  13. 5 Tegaserod Stimulates Canine Small Bowel and Colonic Motility After IV Tegaserod Tegaserod Jejunum Ileum 50 mm Hg Colon 90 0 Minutes Nguyen et al. JPET. 1997;280:1270-1276.

  14. 5 Proximal Distal Rectosigmoid Tegaserod Stimulates CanineColonic Motility and Transit Distribution of colonic isotope at 30 minutes following IV administration of tegaserod 100 80 60 Colonic contents in region, % 40 20 0 Saline Vehicle 0.03 0.1 0.3 Tegaserod dose (mg/kg) Means ± SEM (n = 6) Nguyen et al. J. Pharmacol. Exp. Ther. 1997; 280: 1270-1276

  15. † † Tegaserod 0.6 mg IV Tegaserod 6 mg PO * * Gastric Small bowel emptying transit rate time Effect of Tegaserod on Gastrointestinal Transit in Healthy Subjects 60 40 20 Percent of Control 0 -20 -40 -60 Means ± SEM (n = 12)*P < .05 vs placebo, †P < .005 vs placebo Degen et al. Gastroenterology 2000; AGA Meeting, abstract

  16. Colonic Filling at 6 HoursEffect of Tegaserod in C-IBS 100 80 60 Colonic filing, % 40 20 0 Baseline 1 week Baseline 1 week Placebo Tegaserod Prather, et al. Gastroenterology. 2000.

  17. 5 Effect of Tegaserod on Colonic Transit in C-IBS * Colonic localization of radiotracer 2 1 3 0 4 5 Stool Means ± S.E.M. (n = 12)*P < .05 vs baseline Tegaserod (2 mg b.i.d.) Placebo Prather et al. Gastroenterology 2000; 118: 463-468

  18. 5 Summary: Motor Effects of Tegaserod • Tegaserod mimics the physiologic response to serotonin released from enterochromaffin cells, triggering the peristaltic reflex • Tegaserod promotes motility throughout theGI tract in animals and humans

  19. 5 5-HT4 Receptor Physiology and Pharmacodynamic Effects of Tegaserod • Physiologic role of serotonin (5-HT) and its type-4 receptors (5-HT4) in GI functions • Tegaserod, a partial 5-HT4 receptor agonist, and its pharmacodynamic effects • Effects on motility • Effects on visceral sensitivity

  20. Visceral Sensitivity End-Points for Preclinical Studies in Small Animals • Single afferent fiber recordings • Pseudo-affective measurements: • Animal behavior, eg, withdrawal, writhing • Abdominal contractions • Drop in arterial BP (under anesthesia)

  21. 5 Effect of Tegaserod on Visceral Sensitivity in Cats Static stimulus-response curve (single afferent unit in dorsal root S2 ) Submaximal firing rates at 50 mm Hg 1 ms Ruehl et al. Neurogastroenterol. Mot. 1998; 10: 219-222

  22. 5 Dose-Dependent Inhibition by Tegaserod of Afferent Nerve Activity to Rectal Distension in Cats 100 80 60 40 20 0 * * * * * % of vehicle control EC50 = 0.7 mg/kg Means ± SD (n = 9)*P < .05 0 0.3 0.6 0.9 1.2 1.5 Tegaserod dose (mg/kg IV) Effect inhibited by 5-HT4 antagonist Firing rate at 50 mm Hg distension Schikowski et al. Gastroenterology 1999; 116: A643

  23. 5 Tegaserod Inhibits Abdominal Contractions in Response to Colorectal Distension in Awake Rats * * Mean ± SEM (n = 7)*P < .05 versus vehicle Coelho, et al. Gastroenterology. 2000;118:A835.

  24. Summary: Sensory Effects of Tegaserod During colorectal distension: • Tegaserod reduces visceral afferent firingin cats via stimulation of 5-HT4 receptors • Tegaserod inhibits visceral discomfort/pain in rats

  25. Summary • Serotonin and its 5-HT4 receptors are involved in motor, secretory, and sensory processes in the GI tract • Tegaserod, a partial 5-HT4 receptor agonist, stimulates GI motor functions, and inhibits visceral sensitivity • Tegaserod may influence the sensorimotor dysfunctions and symptoms of constipation-predominant IBS

More Related