How does Constella (linaclotide) work?

From the Guidelines

Constella (linaclotide) works by activating guanylate cyclase-C receptors on the inner surface of the intestine, which increases the production of cyclic guanosine monophosphate (cGMP), resulting in increased intestinal fluid and accelerated GI transit, thereby relieving constipation. This mechanism is supported by a study published in 2023 in the journal Gastroenterology, which found that linaclotide increases cyclic guanosine monophosphate concentrations, resulting in luminal chloride and bicarbonate secretion, and thereby increasing intestinal fluid and accelerating GI transit 1. The typical dose of Constella is 290 mcg taken once daily on an empty stomach, at least 30 minutes before the first meal of the day. Some key points to consider when prescribing Constella include:

• The medication begins working within the first week of treatment for most patients, though some may experience benefits sooner
• Constella is primarily used to treat irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation in adults
• Side effects may include diarrhea, abdominal pain, and flatulence, which typically occur due to the medication's mechanism of increasing intestinal fluid
• Patients should avoid taking Constella if they have a bowel obstruction, as increased intestinal fluid could worsen this condition Additionally, a 2022 study published in Gastroenterology found that linaclotide is an efficacious treatment for IBS-C, with a strong recommendation and high certainty in the evidence of effects 1. It's also worth noting that other studies have confirmed the efficacy of linaclotide in treating constipation, including a 2021 study published in Gut, which found that linaclotide is an efficacious second-line drug for IBS with constipation in secondary care 1. Overall, the evidence suggests that Constella is a effective treatment for constipation, and its mechanism of action is well-supported by the available research.

From the FDA Drug Label

Linaclotide is structurally related to human guanylin and uroguanylin and functions as a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium Activation of GC-C results in an increase in both intracellular and extracellular concentrations 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 fluid and accelerated transit.

Constella (linaclotide) works by acting as a guanylate cyclase-C (GC-C) agonist, which increases the production of cyclic guanosine monophosphate (cGMP) in the intestinal epithelium. This leads to:

• Increased secretion of chloride and bicarbonate into the intestinal lumen
• Activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel
• Increased intestinal fluid and accelerated transit This mechanism of action helps to relieve symptoms of constipation and irritable bowel syndrome with constipation (IBS-C) 2.

From the Research

Mechanism of Action

• Linaclotide (Constella) is a synthetic 14-amino acid peptide that acts as a potent guanylate cyclase C receptor agonist 3, 4, 5, 6, 7.
• It stimulates fluid secretion, increases colonic transit, and reduces abdominal pain by activating intracellular conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate 4, 6.
• Linaclotide has very low oral bioavailability and acts locally in the gastrointestinal tract 3.

Efficacy

• Linaclotide has been shown to be effective in treating irritable bowel syndrome with constipation (IBS-C) and chronic constipation (CC) in multiple clinical trials 3, 4, 5, 6, 7.
• It increases the number of spontaneous bowel movements and stool consistency scores, and provides relief from abdominal discomfort and severity of constipation 4, 6.
• Linaclotide also improves health-related quality of life and reduces abdominal bloating 3, 6.

Safety

• The most common adverse event associated with linaclotide is diarrhea, which is generally controllable by decreasing the dose 3, 4, 6, 7.
• Linaclotide has a good safety profile, with no evidence of drug resistance or serious adverse events 6, 7.
• The efficacy and safety of linaclotide in pediatric patients and in opioid-induced constipation are currently limited and require further study 4.