Guanylyl Cyclase-C Agonists:

Linaclotide - Linzess®

• Indication: in adults for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC).

• MOA: Both linaclotide and its active metabolite are a guanylate cyclase-C (GC￾C) agonists and act locally on the luminal surface of the intestinal epithelium.

• Activation of GC-C results in an increase in both intracellular and extracellularconcentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluidand accelerated transit.

• Contraindicated in pediatric patients up to 6 years ofage. Avoid use in pediatricpatients 6 through 17 years of age.

Linaclotide - Linzess® structure

Plecanatide - Trulance® tablets for oral use

• Indication: treatment of chronic idiopathic constipation (CIC)

• MOA: Guanylate cyclase-C agonist - Both plecanatide and its activemetabolite bind to GC-C and act locally on the luminal surface of theintestinal epithelium

• Adverse Effects: Diarrhea

  • • Metabolized in the GIT to an active metabolite and then degraded within the intestinal lumen to smaller peptides and natural amino acids

• BLACK BOX WARNING:

  • - Risk of serious dehydration in pediatric patients including death by dehydration. Contraindicated in kids less than 6 years old; Avoid use in those who are 6-18years of age.

Plecanatide - Trulance® tablets for oral use structure

Serotonin-4 (5-HT4) receptor agonists: Prucalopride - Motegrity®

• Indications: Chronic idiopathic constipation

• MOA: Serotonin-4 (5-HT4) receptor agonist, stimulates colonic peristalsis, which increases bowel motility.

• Dosing: 2 mg once daily

• Metabolism: Substrate of CYP3A4and P-gp.

• Elimination majorly via renal pathways.

• Suicidal ideation and behavior. Monitor for persistentworsening of depression.

• >2%reported as headache, abdominal pain, N/V, diarrhea, abdominal distension, dizziness, flatulence, and fatigue.

• C/I: Intestinalperforation or obstruction or inflammation

Prucalopride - Motegrity® structure

PIZENSY (lactitol) activity

• MOA: A simple monosaccharide, lactitol exerts an osmotic effectcausing the influx of water into the small intestine leading to a laxativeeffect in the colon

• Indication: Chronic idiopathicconstipation in adults

• Absorption/Excretion:

• • Lactitol is minimally absorbed in the small intestine

• • Unabsorbed lactitol is expected to be degraded into organic acids in the colon and is minimally excreted in the feces

• Adverse Reactions:

  • Diarrhea

  • Upper respiratory infection (9%) of

  • patients in clinical trials

  • Flatulence

• Administration Counseling Points:

  • Supplied as multi-dose packets or bottles which can be mixed with patient's preferred fluid (4-8 oz)

  • Administer with food

PIZENSY (lactitol) structure