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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

Zelnorm

Treatment for IBS

irritable bowel syndrome
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.
serotonin general properties
Serotonin General Properties
  • 5-hydroxytrptamine, 5HT, has numerous subtypes.
  • 5HT4 functions to regulate motility, visceral sensitivity, and intestinal secretion.
mechanism of action of serotonin
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.

intestinal epithelial cells
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.
pathophysiology
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.
tegaserod description
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

mechanism of action of tegaserod
Mechanism of Action of Tegaserod
  • Stimulates release of neurotransmitters
  • Stimulates and mediates peristalic reflex
  • Inhibits visceral sensitivity
  • Stimulates intestinal secretion
metabolism of tegaserod
Metabolism of Tegaserod
  • Acid hydrolysis in the stomach
  • Glucuronidation in the intestines
  • Glucuronidation in the liver
  • Reduction in liver microsomes
formation of glucuronic acid
Formation of glucuronic acid

O

CH2OH

C

OH

O

O

Enzymatic

O

H

OH

Oxidation

OH

OH

OH

OH

OH

OH

glucuronidation
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.
first pathway metabolism
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
liver pathways
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.
intestinal pathway
Intestinal pathway
  • Glucuronidation occurs in the intestines to form M43.8 metabolite.
pharmacokinetics
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.
pharmacokinetics cont
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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