NHE3 Inhibitors for IBS-C: A Primary Care Physician’s Perspective

Physician’s Weekly recently spoke with Linda Girgis, MD, FAAFP, a board-certified family physician in private practice in South River, NJ, about NHE3 inhibitors and their unique method of action (MOA) in treating patients with IBS-C.

PW: How do NHE3 inhibitors work?  

Dr. Girgis: NHE3 inhibitors work by inhibiting sodium-proton exchanger subtype 3 (NHE3) in the gut. NHE3 is found in intestinal epithelium, where its role is NaCl transport and acid-base homeostasis. NHE3 inhibitors block the reabsorption of sodium and lead to more water in the lumen of the gut, which results in softer stools and decreased transit time. 

How does that MOA differ from that of other treatments for IBS-C? 

NHE3 inhibitors work at a different receptor site and mediate sodium exchange rather than chloride as other medications do. 

What makes NHE3s particularly useful in treating IBS-C, considering the condition’s multifactorial pathophysiology? 

NHE3s are useful in IBS-C because they reduce constipation by increasing stool softness and GI transit time. They also work to reduce visceral hypersensitivity and reduce pain. An unintended effect is that they can potentially lower blood pressure in patients with hypertension due to eliminating sodium from the body. 

What evidence is there to support the use of NHE3 inhibitors in treating IBS-C? 

The best evidence comes from the phase 3 T3MPO-2 study published in the American Journal of Gastroenterology. The NHE3 inhibitor in that study was shown to improve symptoms and be generally well tolerated.