Evolving prokinetic therapy: New targets and therapeutic opportunities in gastrointestinal motility disorders

Table 1 Traditional and emerging prokinetics

Drug class	Agent	Mechanism of action	Initial promise	Major adverse effects	Current status	Efficacy limitations
Dopamine antagonists[13,15-19]	Metoclopramide	D2 antagonist, 5-HT4 agonist, 5-HT3 antagonist	First-line therapy for gastroparesis	Tardive dyskinesia, extrapyramidal symptoms	Restricted to < 12 weeks of use	Poor symptom correlation, tolerance
	Domperidone	D2 antagonist (peripheral)	Alternative without CNS effects	Cardiac arrhythmias, QT prolongation	Limited access in United States, cardiac warnings	Moderate efficacy, safety concerns
	Levosulpiride	D2 antagonist, 5-HT4 agonist	Enhanced prokinetic efficacy	Extrapyramidal symptoms, sedation	Limited use	Variable effectiveness
5-HT4 receptor agonists[17,42]	Cisapride	5-HT4 agonist, 5-HT3 antagonist	Potent prokinetic for GERD/gastroparesis	Fatal arrhythmias, sudden cardiac death	Withdrawn from market (2000)	Good efficacy but fatal toxicity
	Tegaserod	5-HT4 agonist, 5-HT1 and 5-HT2b serotonergic antagonist	Improved transit in IBS-C	Ischemic colitis; Cardiovascular risk	Restricted/withdrawn in many regions	Safety concerns
	Prucalopride	5-HT4 agonist, mild affinity for dopamine D4 receptor σ1 receptor	Effective for constipation; some benefit in gastroparesis	Headache, diarrhea; rare neuropsychiatric AEs	Approved (EU/India)	Colonic > gastric effects
	Velusetrag	5-HT4 agonist	Accelerated GE in gastroparesis (Phase 2)	Nausea, diarrhea; rare palpitations	Investigational (fast track)	Limited long-term data
Motilin agonists[20-25]	Erythromycin	Motilin receptor agonist	Strong gastric motility stimulant	Tachyphylaxis, antibiotic resistance	Off-label use, limited efficacy	Rapid tachyphylaxis (2-3 days)
	Mitemcinal	Acid-stable erythromycin derivative; full and selective motilin receptor agonist → MMC induction and enhanced antral contractions	Improved gastric emptying and symptom relief in idiopathic and diabetic gastroparesis	Generally well tolerated; nausea, vomiting, diarrhea, tremors	Investigational	Limited clinical data; studied primarily in gastroparesis
Ghrelin receptor agonists	Relamorelin	Ghrelin receptor agonist → ↑ antral contractions, ↑ GE	Symptom and GE improvement in diabetic gastroparesis	Hyperglycemia, headache	Investigational (fast track)	Injectable; metabolic effects
	Ulimorelin (TZP-102)	Ghrelin receptor agonist	Data scarce/inconclusive	No safety data available	Investigational; ongoing clinical evaluation	Lack of publicly available human efficacy and safety data
Muscarinic agonist[26-28]	Bethanechol	Muscarinic agonist	Early prokinetics for reflux	Cholinergic side effects	Largely abandoned	Weak prokinetic effect
	Acotiamide	Novel acetylcholinesterase inhibitor	Improved gastric emptying and accommodation in FD	Minimal; headache, diarrhea	Approved in Japan, India and few other countries	Limited availability

Comprehensive synthesis of established and novel prokinetic therapies, outlining their underlying mechanisms of action, clinical applications, associated safety considerations, and inherent therapeutic limitations. 5-HT₁: 5-Hydroxytryptamine type 1 receptor; 5-HT2b: 5-Hydroxytryptamine type 2b receptor; 5-HT₃: 5-Hydroxytryptamine type 3 receptor; 5-HT₄: 5-Hydroxytryptamine type 4 receptor; AEs: Adverse events; CNS: Central nervous system; D2: Dopamine type 2 receptor; EU: European union; FD: Functional dyspepsia; GE: Gastric emptying; GERD: Gastroesophageal reflux disease; IBS-C: Irritable bowel syndrome with constipation; MMC: Migrating motor complex.