Constipation-predominant irritable bowel syndrome: A review of current and emerging drug therapies

Table 1 Main types of pharmacologic laxatives

Type	Agents	Mechanism of action	Most common adverse events
Bulking agents	Psyllium	Increase in stool bulk and reduction in consistency by luminal water binding	Bloating
	Methylcellulose		Flatulence
	Calcium polycarbophil
Stool softeners	Docusate potassium	Softening and lubrication of stools by increasing water secretion	Nausea
(surfactants)	Docusate sodium		Vomiting
	Docusate calcium		Abdominal pain/cramps
			Rectal urgency
Osmotic laxatives	Milk of Magnesia (magnesium hydroxide)	Osmotic water retention, decreased stool consistency, and increase fecal volume and peristalsis	Sweet taste
	Magnesium citrate		Nausea
	Magnesium sulphate		Bloating
	Sodium picosulphate/magnesium citrate (Picoprep®)		Flatulence
	Lactulose/lactilol		Abdominal pain/cramps
	Sorbitol		Electrolyte disturbances (?)
	Polyethylene glycol (macrogol)
Stimulant laxatives	Anthraquinones	Luminal water retention through activation of CAMP, and induction of colonic contractions by acting on enteric nerves	Abdominal pain/cramps
	Senna		Dehydration
	Cascara		Electrolyte disturbances
	Bisacodyl		Muscle cramps
	Phenolphthalein		Melanosis coli/colonic inertia (?)

CAMP: Cyclic adenosine monophosphate.

Table 2 Chemical and clinical characteristics of discontinued/failed prokinetics

	Cisapride	Renzapride	Tegaserod
Chemical structure	Piperidinyl benzamide	Benzamide derivative	Indole carboxaldehyde derivative
Target receptors	Nonselective 5-HT4 agonist and 5-HT3 antagonist	Full 5-HT4 agonist and antagonist of 5-HT3 and 5-HT2b	5-HT4 and 5-HT1 partial agonist
Mechanism of action/pharmacodynamic effects	Local acetylcholine release;	Local acetylcholine release;	Augmentation of the peristaltic reflex;
	Acceleration of GI transit	Acceleration of GI transit	Enhanced intestinal secretion;
			Reduced sensitivity to rectal distension
Most common adverse events	Diarrhea	Diarrhea	Diarrhea
	Abdominal pain	Abdominal pain	Abdominal pain
		Headache	Headache
		Flatulence	Flatulence
Safety	Prolongation of QTc interval and fatal arrhythmias	No prolongation of QTc interval	Increased risk of serious ischemic cardiac events
Approval status	Approved in 1993; Withdrawn in 2000	Phase 3 RCTs terminated due to insufficient efficacy	Approved in 2002 for IBS-C (not in EU) and in 2004 for CC; Withdrawn in 2007

CC: Chronic constipation; EU: European Union; GI: Gastrointestinal; IBS-C: Constipation predominant-irritable bowel syndrome; QTc: Corrected QT interval; RCT: Randomized controlled trial; 5-HT: 5-hydroxytryptamine.

Table 3 Chemical and clinical characteristics of novel prokinetic agents

	Prucalopride	Naronapride	Velusetrag	ROSE-010
Chemical structure	Dihydrobenzofuran carboxamide	Benzamide	Dihydroxyquinoline-carboxamide	Glucagon-related peptide
Target receptor/affinity	High selectivity and affinity for 5-HT4 (> 150-fold)	5-HT4 full agonist in the GI tract; partial agonist in the heart	Potent selective agonist of 5-HT4 with high affinity (500-fold)	GLP-1 analogue
Pharmacodynamic effects	Accelerated colonic transit in health and CC	Accelerated colonic transit in health	Dose-dependent acceleration of colonic transit in health	Acceleration of colonic transit; antinociceptive effect in IBS-C
Most common adverse events	Diarrhea	Diarrhea	Diarrhea	Nausea
	Nausea	Headache	Nausea	Headache
	Headache		Headache
	Abdominal pain		Vomiting
Approval status/stage of development	Approved for CC in EU in 2009 and in Canada in 2011	Phase 2 RCTs in CC completed	Phase 2 RCTs in CC completed	Phase 2 RCTs in IBS-C completed

CC: Chronic constipation; EU: European Union; GI: Gastrointestinal; GLP-1: Glucagon like peptide-1; IBS-C: Constipation-predominant irritable bowel syndrome; RCT: Randomized controlled trial; 5HT: 5-hydroxytryptamine.

Table 4 Chemical and clinical characteristics of prosecretory agents

Drug	Lubiprostone	Linaclotide	Plecanatide
Chemical structure	A prostone, bicyclic fatty acid (metabolite of prostaglandin E1)	14-amino acid peptide, analogue of guanylin	Analogue of uroguanylin
Target receptor/mechanism of action	Activation of ClC-2 by direct action on epithelial cells provoking intestinal fluid secretion, also mediated by CFTR	Binding to GC-C with stimulation of cGMP and CFTR-mediated secretion; desensitization of afferent pain fibers mediated by production of extracellular cGMP	GC-C receptor activation with CFTR-mediated secretion
Pharmacodynamic effects	Accelerated small bowel and colonic transit	Dose-related acceleration of colonic transit	Probable acceleration of colonic transit
Most common adverse events	Nausea	Dose-dependent diarrhea	Dose-independent diarrhea
	Diarrhea		Nausea
	Abdominal pain
Potential other beneficial effects	Mucosal protection	Antineoplastic	-
Cost	AWP is $296 for one month supply	AWP is $255 for 30 capsules	-
Approval status/stage of development	United States FDA-approved for women with IBS-C and men and women with CC	United States FDA-approved for both IBS-C and CC EMA-approved for IBS-C only	Phase 2b RCT in CC completed; Phase 3 RCT in CC recruiting patients; Phase 2 RCT in IBS-C recruiting patients

AWP: Average wholesale price; CC: Chronic constipation; CFTR: Cystic fibrosis transmembrane conduction regulator; cGMP: Cyclic guanosine monophosphate; ClC-2: Chloride channel-2; EMA: European Medicines Agency; FDA: Food and Drug Administration; GC-C: Guanylate cyclase-C; IBS-C: Constipation-predominant irritable bowel syndrome; RCT: Randomized controlled trial.

Table 5 Chemical and clinical characteristics of bile acid modulators

	Chenodeoxycholate	Elobixibat
Chemical structure	Sodium chenodeoxycholic acid (primary bile acid)	Enantiomer of 1,5-benzothiazepine
Mechanism of action	Deconjugation to secondary bile acids, thus inducing colonic secretion and propulsive contractions	IBAT inhibition resulting in delivery of endogenous bile acids to the colon, thus inducing colonic secretion and propulsive contractions
Pharmacodynamic effects	Accelerated colonic transit	Dose-dependent acceleration of colonic transit
Most common adverse events	Diarrhea	Diarrhea
	Abdominal cramping/pain	Abdominal cramping/pain
	Nausea
Potential other beneficial effects	Probable lowering of LDL	Lowering of LDL and cholesterol
Stage of development	Phase 3 RCT in IBS-C completed	Phase 3 RCTs in CC, completed; extended safety and tolerability RCTs enrolling

CC: Chronic constipation; IBAT: Ileal bile acid transporter; IBS-C: Constipation-predominant irritable bowel syndrome; LDL: Low-density lipoprotein; RCT: Randomized controlled trial.

Table 6 Chemical and clinical characteristics of drugs approved for other gastrointestinal indications and currently investigated for constipation-predominant irritable bowel syndrome

	Itopride	Neomycin/Rifaximin
Brand name	Ganaton®	Neomycin: Neo-Fradin®
		Rifaximin: Xifaxan®
Chemical structure	Benzamide derivative	Neomycin: aminoglycoside
		Rifaximin: semisynthetic antibiotic based on rifampicin
Mechanism of action	Dopamine D2 antagonist and acetylcholinesterase inhibitor	Neomycin: inhibition of protein synthesis
		Rifaximin: inhibition of bacterial RNA synthesis
Pharmacodynamic effects	Gastrokinetic;	Eradication of methane; accelerated intestinal transit (?)
	Acceleration of intestinal transit (?)
Most common adverse events	Diarrhea	Neomycin:
	Headache	Neurotoxicity
	Hyperprolactinemia	Ototoxicity
		Nephrotoxicity
		Rifaximin:
		Headache
		Nausea
		Dizziness
		Fatigue
Approval status/stage of development	Approved in Japan for functional dyspepsia;	FDA-approved for hepatic encephalopathy and traveler’s diarrhea;
	Phase 2 RCT in IBS-C completed in the United States	Phase 2 efficacy RCT in methane + IBS-C patients, comparing neomycin vs combination rifaximin and neomycin (completed)

FDA: Food and Drug Administration; IBS-C: Constipation-predominant irritable bowel syndrome; RCT: Randomized controlled trial.

Table 7 Quality of evidence supporting different pharmacologic agents for constipation-predominant irritable bowel syndrome and chronic constipation

Pharmacologic agent	Quality of evidence for IBS-C	Quality of evidence for CC
Laxatives
Psyllium	No RCTs	Moderate
Docusate sodium	No RCTs	Low
Lactulose	No RCTs	Moderate
PEG	Moderate	High
Senna	No RCTs	Low
Bisacodyl	No RCTs	Moderate
Prokinetics
Prucalopride	No RCTs	High
Naronapride	No RCTs	Low
Velusetrag	Low	Low
Rose-010	Moderate	No RCTs
Secretagogues
Lubiprostone	High	High
Linaclotide	High	High
Plecanatide	Low	Low
Bile acid modulators
CDC	Low	Low
Elobixibat	No RCTs	Moderate

The quality of evidence was assessed according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system[86], which defines study quality as high (further research is very unlikely to change confidence in the estimated effect); moderate (further research is likely to have an important impact on confidence in the estimated effect and may change the estimate); low (further research is very likely to have an important impact on confidence in the estimated effect and is likely to change the estimate); or very low (any estimate of effect is very uncertain). CC: Chronic constipation; CDC: Chenodeoxycholate; IBS-C: Constipation-predominant irritable bowel syndrome; PEG: Polyethylene glycol; RCT: Randomized controlled trials.