Physician’s Weekly recently spoke with Lin Chang, MD, AGAF, lead author of the 2022 American Gastroenterological Association (AGA) Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation (IBS-C)—about NHE3 inhibitors and their unique method of action (MOA) in treating patients with IBS-C.
PW: How do NHE3 inhibitors work?
Dr. Chang: NHE3 inhibition blocks the absorption of sodium from the small intestine and colon and allows an increase in water secretion into the intestinal lumen, which helps accelerate intestinal transit time and improves constipation and abdominal symptoms.
How does that MOA differ from that of other treatments for IBS-C?
Tenapanor is a first-in-class, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3 (NHE3), which is expressed on the apical surface of the small intestine and colon and is responsible for the absorption of sodium, rather than increasing secretion of electrolytes into the intestinal lumen like the secretagogues, linaclotide and plecanatide. There is also evidence that tenapanor can normalize alterations in intestinal permeability, which is thought to contribute to improvements in abdominal pain.
What makes NHE3s particularly useful in treating IBS-C, considering the condition’s multifactorial pathophysiology?
This medication has multiple mechanisms of action that can improve the multi-symptom disorder of IBS-C, namely abdominal pain, bloating, and constipation.
What evidence is there to support the use of NHE3 inhibitors in treating IBS-C?
Three placebo-controlled, randomized controlled trials (one phase 2b and two phase 3) have evaluated the efficacy and safety of tenapanor in patients with IBS-C. Compared with placebo, patients who received tenapanor experienced greater symptom relief, improvements in abdominal pain, and complete spontaneous bowel movement frequency.