Linaclotide and plecanatide are minimally absorbed, short amino acid peptides that stimulate intestinal chloride secretion through a different mechanism by binding to and activating guanylate cyclase-C on the luminal surface. This leads to increased intracellular and extracellular cyclic guanosine monophosphate (cGMP) with activation of the cystic fibrosis transmembrane conductance regulator (CFTR), followed by chloride-rich secretion and acceleration of intestinal transit. Both agents are approved for the treatment of chronic constipation (linaclotide 145 mcg orally once daily; plecanatide 3 mg orally once daily); linaclotide is also approved for the treatment of irritable bowel syndrome with constipation (290 mcg orally once daily). These agents result in an average increase of 1–2 bowel movements per week that usually occurs within the first week of treatment. Upon discontinuation of the drug, bowel movement frequency returns to normal within 1 week. The most common side effect is diarrhea, which occurs in up to 20% of patients, with severe diarrhea in 2%. These drugs have negligible absorption at standard doses. Both drugs are contraindicated in pediatric patients because of reports of increased mortality in juvenile mice from dehydration. (Crofelemer is a small molecule with the opposite effect: it is an inhibitor of the CFTR channel and has recently been approved for the treatment of HIV-drug-induced diarrhea.)
Acute and chronic therapy with opioids may cause constipation by decreasing intestinal motility, which results in prolonged transit time and increased absorption of fecal water (see Chapter 31). Use of opioids after surgery for treatment of pain as well as endogenous opioids also may prolong the duration of postoperative ileus. These effects are mainly mediated through intestinal mu (μ)-opioid receptors. Two selective antagonists of the μ-opioid receptor are commercially available: methylnaltrexone bromide and alvimopan. Because these agents do not readily cross the blood-brain barrier, they inhibit peripheral μ-opioid receptors without impacting analgesic effects within the central nervous system. Methylnaltrexone is approved for the treatment of opioid-induced constipation in patients receiving palliative care for advanced illness who have had inadequate response to other agents. It is administered as a subcutaneous injection (0.15 mg/ kg) every 2 days. Alvimopan is approved for short-term use to shorten the period of postoperative ileus in hospitalized patients who have undergone small or large bowel resection. Alvimopan (12 mg capsule) is administered orally within 5 hours before surgery and twice daily after surgery until bowel function has recovered, but for no more than 7 days. Because of possible cardiovascular toxicity, alvimopan currently is restricted to short-term use in hospitalized patients only.
Stimulation of 5-HT4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitonin gene-related peptide, which stimulates second-order enteric neurons to promote the peristaltic reflex (Figure 62–4). These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide).