Inhibition of ileal bile acid transporter: An emerging therapeutic strategy for chronic idiopathic constipation

Table 1 Most common types of drugs used for the treatment of chronic idiopathic constipation and constipation-predominant irritable bowel syndrome

Drug class	Generic name	Phase of clinical trial/approval status	Proposed mechanism of action	Therapeutic effect	Most frequent adverse effect	Ref.
Secretagogue	Linaclotide	III/FDA approval (2012)	GC-C agonist	Antinociceptive and antihyperalgesic. Increases intestinal fluid, accelerates GI transit, reduces abdominal pain	Mild or moderate diarrhea	[4,8-11]
	Lubiprostone	III-IV/FDA approval (2008)	CIC-2 activator	Promotes intestinal fluid secretion, increases SBM frequency, reduces abdominal bloating and discomfort	Nausea, diarrhea, abdominal distention, headache	[8,12-14]
	Plecanatide	II, III for CIC and I for IBS-C	GC-C agonist	Facilitates bowl movements, stimulates water secretion, improves stool consistency and frequency	Diarrhea (mild or moderate), nausea, abdominal discomfort, abdominal pain, vomiting (at the highest doses)	[12,15,16]
Prokinetic	Tegaserod	Withdrawn by the FDA in 2007 due to risk of adverse cardiovascular effects	Selective partial 5-HT4 agonist	Stimulates motility in the upper and lower GI tract, reduces visceral sensitivity and pain, improves stool consistency	Diarrhea, cardiovascular effects (angina, myocardial infarction, and cerebrovascular events)	[12,17-19]
				Administered twice daily increases gastric emptying rate
				Smooth muscle relaxant, reduces colonic pseudo-obstruction and constipation
	Renzapride	II and III for IBS-C; remains under evaluation	Full 5-HT4 agonist and 5-HT3 receptor antagonist	Prokinetic and stimulatory effect on GI transit, improves stool consistency	Diarrhea, abdominal pain, constipation, nausea	[8,20-22]
	Prucalopride	III, undergoing clinical trials	5-HT4 agonist	Improves the frequency of SBM, reduces abdominal discomfort	Headache, nausea, abdominal pain, diarrhea	[12,14,20]
	Velusetrag, naronapride	Completed Phase II	5-HT4 receptor agonist	Accelerates colonic and orocecal transit, increases SBM, normalizes stool consistency	Diarrhea, headache, nausea	[23-25]
Laxatives	Lactulose, sorbitol, polyethylene glycol, magnesium citrate	Approved	Osmotic water retention, stimulant	Increases fecal volume and peristalsis	Bloating, cramping, and flatulence	[17,26-28]
Bile acid modulators	Chenodeoxycholate	II, remains under evaluation	Intracellular activation of adenylate cyclase, inhibition of apical Cl-/OH - exchange	Accelerates colonic transit, improves stool consistency	Lower abdominal cramping, diarrhea	[18,27]

CIC: Chronic idiopathic constipation; FDA: Food and Drug Administration; GC-C: Guanylate cyclase C; GI: Gastrointestinal; IBS-C: Constipation-predominant irritable bowel syndrome; SBM: Spontaneous bowel movement.