Jadallah KA, Kullab SM, Sanders DS. Constipation-predominant irritable bowel syndrome: A review of current and emerging drug therapies. World J Gastroenterol 2014; 20(27): 8898-8909 [PMID: 25083062 DOI: 10.3748/wjg.v20.i27.8898]
Corresponding Author of This Article
Khaled A Jadallah, MD, Assistant Professor of Medicine, Department of Internal Medicine, King Abdullah University Hospital, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan. khaled-j@just.edu.jo
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Topic Highlight
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Jul 21, 2014; 20(27): 8898-8909 Published online Jul 21, 2014. doi: 10.3748/wjg.v20.i27.8898
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 (?)
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
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
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
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
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)
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
Citation: Jadallah KA, Kullab SM, Sanders DS. Constipation-predominant irritable bowel syndrome: A review of current and emerging drug therapies. World J Gastroenterol 2014; 20(27): 8898-8909