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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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Zelnorm l.jpg

Zelnorm

Treatment for IBS


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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.



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Serotonin General Properties

  • 5-hydroxytrptamine, 5HT, has numerous subtypes.

  • 5HT4 functions to regulate motility, visceral sensitivity, and intestinal secretion.


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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.


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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.




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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.



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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


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Mechanism of Action of Tegaserod

  • Stimulates release of neurotransmitters

  • Stimulates and mediates peristalic reflex

  • Inhibits visceral sensitivity

  • Stimulates intestinal secretion


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Metabolism of Tegaserod

  • Acid hydrolysis in the stomach

  • Glucuronidation in the intestines

  • Glucuronidation in the liver

  • Reduction in liver microsomes



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Formation of glucuronic acid

O

CH2OH

C

OH

O

O

Enzymatic

O

H

OH

Oxidation

OH

OH

OH

OH

OH

OH


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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.


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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


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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.


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Intestinal pathway

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


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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.


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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.


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