From the Guidelines
Linaclotide is a guanylate cyclase-C agonist that increases intestinal fluid secretion and accelerates bowel transit time, and it is recommended to be used in patients with irritable bowel syndrome with constipation (IBS-C) at a dosage of 290 mg once daily, as stated in the AGA clinical practice guideline 1.
Mechanism of Action
Linaclotide works by stimulating the GC-C receptor on enterocytes, resulting in intestinal chloride and bicarbonate secretion, and inhibiting colonic nociceptors in animal models 1. This leads to increased fluid in the bowels and faster transit of stool.
Dosage and Administration
The typical dose of linaclotide is 145 mcg once daily for chronic constipation or 290 mcg once daily for IBS-C, taken on an empty stomach at least 30 minutes before the first meal of the day 1.
Side Effects and Contraindications
Common side effects of linaclotide include diarrhea, abdominal pain, and flatulence 1. The medication is contraindicated in individuals with known or suspected mechanical gastrointestinal obstruction 1.
Clinical Use
Linaclotide has been demonstrated to improve abdominal symptoms of bloating, discomfort, and pain in IBS-C trials, making it a useful option for individuals with these coexisting symptoms 1. Patients should be instructed to take linaclotide without food, at least 30 minutes before the first meal of the day. Some key points to consider when prescribing linaclotide include:
- The use of linaclotide might be associated with diarrhea leading to discontinuation or dose reduction, although this is not very common 1
- There were no clear differences in outcomes among individuals older than 65 years in clinical trials, although the sample size was too small to support formal analysis on differences in outcomes related to age 1
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.
Linaclotide works by:
- Binding to guanylate cyclase-C (GC-C) and acting locally on the luminal surface of the intestinal epithelium
- Increasing intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP)
- Stimulating secretion of chloride and bicarbonate into the intestinal lumen through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel
- Resulting in increased intestinal fluid and accelerated transit 2 2 2
From the Research
Mechanism of Action
- Linaclotide acts on guanylate cyclase-C receptors on the luminal membrane to increase chloride and bicarbonate secretions into the intestine and inhibit the absorption of sodium ions, thus increasing the secretion of water into the lumen and improving defecation 3, 4.
- This results in generation of cyclic guanosine monophosphate (cGMP), which stimulates chloride secretion, resulting in increased luminal fluid secretion and an acceleration of intestinal transit 4.
- Linaclotide also decreased visceral hypersensitivity in animal models 4.
Therapeutic Uses
- Linaclotide is indicated for the treatment of adults with chronic constipation (CC) and constipation-predominant irritable bowel syndrome (IBS-C) 3, 4, 5, 6.
- It is approved by the Food and Drug Administration (FDA) for oral once-daily administration at doses of 145 μg for CC and 290 μg for IBS-C 3.
- Linaclotide has been shown to be effective in increasing weekly spontaneous bowel movements and complete spontaneous bowel movements (CSBMs) while reducing abdominal pain in patients with CC and IBS-C 3, 4, 5, 6.
Safety and Efficacy
- The most common adverse effect of linaclotide is diarrhea, which was reported in 16-20% of clinical trial participants 3, 4.
- Linaclotide has a good safety profile, with diarrhea being the main side effect 6.
- Linaclotide is minimally absorbed into the systemic circulation, and its adverse effects are generally mild and confined to the gastrointestinal tract 3, 4.
Clinical Recommendations
- Linaclotide is recommended to be taken continuously and not sporadically 5.
- Patients should be warned about the risk of diarrhea and given choices concerning how to deal with this possible side effect 5.
- The absence of tachyphylaxis or potential risks implies that linaclotide treatment can be maintained for long periods of time 5.