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Zelnorm. Treatment for IBS. Irritable Bowel Syndrome. Debilitating gastrointestinal syndrome which produces symptoms of bloating, abdominal pain or discomfort, diarrhea and/or constipation. 2:1 predominance toward females. Affects 10%+ North Americans.

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  1. Zelnorm Treatment for IBS

  2. Irritable Bowel Syndrome • Debilitating gastrointestinal syndrome which produces symptoms of bloating, abdominal pain or discomfort, diarrhea and/or constipation. • 2:1 predominance toward females. • Affects 10%+ North Americans. • Symptoms can be intermittant or continual.

  3. Structure of serotonin

  4. Serotonin General Properties • 5-hydroxytrptamine, 5HT, has numerous subtypes. • 5HT4 functions to regulate motility, visceral sensitivity, and intestinal secretion.

  5. Mechanism of Action of Serotonin • 5HT4 receptors on intestinal cells • Transmembrane domain receptor • Elicit the depolarizing action of serotonin, which results in the release of neuro- transmitters from enteric neurons, which propel contents through the GI tract.

  6. Intestinal epithelial cells • 90% of serotonin is found in the enterochromaffin cells, which are found in the epithelial cell layer. • 10% of serotonin is found in enteric nerves. • Trace amount found in smooth muscle cells.

  7. Intestinal epithelial cells – 20X

  8. Serotonin pathway

  9. Pathophysiology • If a patient with IBS has a large or small bowel biopsy the findings may show no changes or reflect an increase in lymphocytes. • IBS episodes may be triggered by a gastrointestinal viral infections.

  10. Structure of Tegaserod

  11. Tegaserod Description • 5HT4 receptor partial agonist which bonds with high affinity to 5HT4 receptors Hydrogen maleate salt 3-(5methoxy-1H-indol-3-ylmethylene) N-pentyl carbazimidamide hydrogen maleate C16H23N5O Molecular weight of 417.47

  12. Mechanism of Action of Tegaserod • Stimulates release of neurotransmitters • Stimulates and mediates peristalic reflex • Inhibits visceral sensitivity • Stimulates intestinal secretion

  13. Metabolism of Tegaserod • Acid hydrolysis in the stomach • Glucuronidation in the intestines • Glucuronidation in the liver • Reduction in liver microsomes

  14. Metabolites

  15. Formation of glucuronic acid O CH2OH C OH O O Enzymatic O H OH Oxidation OH OH OH OH OH OH

  16. Glucuronidation • Process which removes many toxic chemicals including aeromatic amines. • Is a major way of converting drugs to forms that can be excreted into urine or bile.

  17. First Pathway Metabolism • Hydrolysis in the stomach starts with cleavage that yields an aldehyde • Aldehyde is hydrolysed to a carboxylic acid • The hydroxyl group through enzymatic oxidation is conjugated with glucuronic acid. • This metabolite M29.0 is found in plasma

  18. Liver pathways • The formation of O-desmethyl tegaserod through the liver microsomes, which is a slow process, M52.8, due to the presence of quinidine. • Metabolites in the liver which have been glucuronidation of the 3 different amide groups to yield M43.2, M43.8, M45.3 • These metabolites are excreted into bile.

  19. Intestinal pathway • Glucuronidation occurs in the intestines to form M43.8 metabolite.

  20. Pharmacokinetics • Rapidly absorbed in the fasting state • Peak plasma concentrations occur within 1.5 hours. • Terminal half life 11+/- 5 hours • 2/3 excreted unchanged in the feces and 1/3 in urine • Only negligible amounts cross the blood/brain barrier.

  21. Pharmacokinetics cont. • Patients with mild to moderate renal impairment can use Tegaserod • Patients with mildly reduced liver function may use Tegaserod • No dose adjustment needed for age or gender.