GI stimulants

Generic and Brand Names

• Metoclopramide — Reglan, Maxolon

• Domperidone — Motilium

• Prucalopride — Motegrity, Resolor

• Tegaserod — Zelnorm

• Erythromycin (off-label prokinetic) — generics

• Neostigmine (for acute colonic pseudo-obstruction) — Bloxiverz

• Bethanechol — Urecholine

• Cisapride (restricted/withdrawn in many regions) — Propulsid

• Mosapride — Gasmotin

• Itopride — Ganaton

• Adjacent motility-promoters used by indication

  • PAMORAs for opioid-induced constipation: Methylnaltrexone (Relistor), Naloxegol (Movantik), Naldemedine (Symproic)

  • Secretagogues for chronic constipation/IBS-C: Lubiprostone (Amitiza), Linaclotide (Linzess/Constella), Plecanatide (Trulance)

Class

• Gastrointestinal stimulants and prokinetics that enhance gastric or intestinal motility via dopamine D2 antagonism, 5-HT4 receptor agonism, motilin receptor agonism, muscarinic or acetylcholinesterase mechanisms.

• Adjacent categories (PAMORAs, secretagogues) increase bowel movements by reversing opioid effects or by chloride-mediated secretion; included for clinical context where “stimulant” use overlaps.

Mechanism of Action

• Metoclopramide: Central/peripheral D2 antagonism; 5-HT4 agonism and 5-HT3 antagonism at higher doses; enhances ACh release in myenteric plexus → ↑ gastric emptying, ↑ LES tone, ↑ small-bowel transit.

• Domperidone: Peripheral D2 antagonism (minimal CNS penetration) → ↑ gastric emptying and antiemesis via chemoreceptor trigger zone outside BBB.

• Prucalopride: Highly selective 5-HT4 receptor agonist → prokinetic effect throughout colon; accelerates colonic transit.

• Tegaserod: Partial 5-HT4 agonist with 5-HT1 effects → ↑ peristaltic reflex and intestinal secretion.

• Erythromycin: Motilin receptor agonist (macrolide class effect) → strong antral contractions; tachyphylaxis common.

• Neostigmine: Acetylcholinesterase inhibitor → ↑ ACh at neuromuscular junction of colon; effective in acute colonic pseudo-obstruction (Ogilvie).

• Bethanechol: Muscarinic agonist → ↑ GI tone and motility (limited modern use).

• Cisapride: 5-HT4 agonist (and 5-HT3 effects) → broad prokinetic; high QT/TdP risk limits availability.

• Mosapride: Peripheral 5-HT4 agonist (minimal 5-HT3) → prokinetic (regional availability).

• Itopride: D2 antagonist + acetylcholinesterase inhibition → ↑ gastric motility (regional availability).

• PAMORAs: Peripheral μ-opioid receptor antagonists → reverse opioid-induced gut hypomotility without affecting analgesia.

• Secretagogues (lubiprostone, linaclotide, plecanatide): Chloride channel/C-type guanylate cyclase agonism → ↑ intestinal fluid and transit.

Indications

• Gastroparesis (diabetic/post-surgical): Metoclopramide first-line short-term; erythromycin as short-course/bridge; domperidone where available; itopride/mosapride regionally.

• GERD adjunct (symptomatic, short-term): Metoclopramide in selected refractory cases; avoid long-term.

• Nausea/vomiting adjunct where delayed gastric emptying suspected: Metoclopramide, domperidone (regional).

• Chronic idiopathic constipation (CIC): Prucalopride first-line prokinetic option; secretagogues as alternatives/complements.

• IBS-C: Tegaserod (restricted use in women <65 without CV risk); secretagogues as alternatives.

• Acute colonic pseudo-obstruction (Ogilvie): Neostigmine with cardiac monitoring when conservative measures fail.

• Opioid-induced constipation refractory to laxatives: PAMORAs.

• Postoperative ileus: Limited, mixed evidence for prokinetics; support care is primary.

Dosage and Administration

• Metoclopramide: 10 mg PO up to 30 minutes before meals and at bedtime (max 40 mg/day); IV 10 mg for acute use. Limit duration to ≤12 weeks to reduce tardive dyskinesia risk. Renal impairment: reduce dose.

• Domperidone: 10 mg PO three times daily 15–30 minutes before meals; some use 20 mg TID. QT risk; avoid potent CYP3A4 inhibitors.

• Prucalopride: 2 mg PO once daily; 1 mg once daily if severe renal impairment (CrCl <30 mL/min).

• Tegaserod: 6 mg PO twice daily ≥30 minutes before meals; restricted program criteria apply.

• Erythromycin: 125–250 mg PO three times daily before meals or 3 mg/kg IV q8h as prokinetic; tachyphylaxis in days–weeks.

• Neostigmine (ACPO): 2 mg IV slow push over 3–5 minutes with continuous ECG; atropine at bedside; repeat once if needed.

• Bethanechol: 10–25 mg PO three or four times daily; limited efficacy and cholinergic adverse effects.

• Cisapride (where accessible under restricted programs): 5–10 mg PO before meals and at bedtime; stringent ECG/interaction screening.

• Mosapride: 5 mg PO three times daily (regional).

• Itopride: 50 mg PO three times daily (regional).

• PAMORAs/Secretagogues: Per product labels (see “Comparison Table 2” notes).

Monitoring

• Efficacy: Symptom diaries (nausea, early satiety, bloating), gastric residuals if inpatient, bowel movement frequency/consistency for constipation.

• Safety:

  • Neurologic (metoclopramide) for extrapyramidal symptoms and tardive dyskinesia.

  • ECG/QT with domperidone, cisapride, tegaserod, macrolides; electrolytes (K, Mg).

  • Cardiovascular evaluation before tegaserod.

  • Heart rate/bronchospasm for neostigmine; have atropine available.

  • Renal function for prucalopride dosing; hepatic function for erythromycin interactions.

Contraindications

• Metoclopramide: GI hemorrhage/obstruction/perforation; pheochromocytoma; history of tardive dyskinesia; seizure disorders (relative).

• Domperidone: Known QT prolongation, significant cardiac disease, potent CYP3A4 inhibitors, prolactinoma, GI obstruction/perforation.

• Prucalopride: Intestinal perforation/obstruction, toxic megacolon/megarectum; severe dialysis-dependent renal failure without dose guidance.

• Tegaserod: History of MI, stroke, TIA, unstable angina; severe hepatic/renal impairment; bowel obstruction.

• Erythromycin: Significant QT prolongation or interacting QT-prolonging/CYP3A4 inhibitor combinations.

• Neostigmine: Mechanical obstruction, peritonitis, bradycardia, recent MI, bronchospasm, urinary obstruction.

• Bethanechol: Asthma, bradycardia, hypotension, peptic ulcer, mechanical GI/urinary obstruction.

• Cisapride: Known/prolonged QT, significant cardiac disease, potent CYP3A4 inhibitors.

Precautions

• Metoclopramide: Use minimal effective dose/duration; elderly and females higher TD risk.

• Domperidone: Use lowest effective dose; baseline ECG if risk factors; avoid >30 mg/day in many regions.

• Prucalopride: Headache/diarrhea common initially; reassess efficacy at 4 weeks.

• Tegaserod: Restrict to low CV-risk women <65; counsel on ischemic symptoms.

• Erythromycin: Rapid tachyphylaxis; significant drug–drug interaction potential.

• Neostigmine: Give in monitored setting; atropine and resuscitation readiness mandatory.

• Cisapride: Only under restricted access with rigorous ECG and interaction screening.

Adverse Effects

• Metoclopramide: Somnolence, fatigue, restlessness, acute dystonia, akathisia; tardive dyskinesia with chronic use; hyperprolactinemia.

• Domperidone: Headache, dizziness, dry mouth, galactorrhea; QT prolongation, rare serious ventricular arrhythmias/sudden death.

• Prucalopride: Headache, nausea, diarrhea, abdominal pain; rare mood changes.

• Tegaserod: Diarrhea, abdominal pain; rare ischemic cardiovascular events.

• Erythromycin: Nausea, cramps, diarrhea; QT prolongation; hepatotoxicity; drug interactions.

• Neostigmine: Bradycardia, bronchospasm, salivation, abdominal cramps; cholinergic crisis if overdosed.

• Bethanechol: Sweating, salivation, flushing, hypotension, bronchospasm.

• Cisapride: QT prolongation, torsades de pointes.

• Mosapride/Itopride: Generally mild GI upset; monitor QT interactions with mosapride.

Drug Interactions

• QT-prolonging combinations: Macrolides, azoles, fluoroquinolones, antipsychotics, certain antidepressants increase risk with domperidone/cisapride/tegaserod/erythromycin.

• CYP3A4: Erythromycin (inhibitor) raises levels of many drugs; domperidone/cisapride levels rise with strong CYP3A4 inhibitors (azole antifungals, protease inhibitors, clarithromycin).

• Dopaminergic agents: Antagonism with Parkinson’s therapies (metoclopramide, domperidone).

• Anticholinergics: Antagonize prokinetic effects of cholinergic agents and metoclopramide.

• Opioids: Worsen GI hypomotility; consider PAMORA rather than escalating prokinetics.

Overdose

• Metoclopramide: Extrapyramidal reactions (treat with anticholinergics or diphenhydramine), sedation, hypotension.

• Domperidone/Cisapride: Ventricular arrhythmias; urgent ECG and electrolyte correction.

• Neostigmine/Bethanechol: Cholinergic crisis (salivation, miosis, bronchospasm, bradycardia) — treat with atropine, airway support.

• Erythromycin: Severe GI effects, hepatotoxicity, arrhythmias in predisposed patients.

Patient Counselling

• Take metoclopramide/domperidone 15–30 minutes before meals; avoid exceeding prescribed duration for metoclopramide.

• Report palpitations, syncope, or new neurologic symptoms immediately.

• Maintain hydration; small frequent meals in gastroparesis.

• Do not combine with over-the-counter antihistamines/anticholinergics without advice.

• If on prucalopride, expect early headache/diarrhea that often improve within a week; continue unless severe.

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Comparison Table 1 — Core GI Prokinetics

Agent	Primary Mechanism	Usual Adult Dose	Key Indications	Major Risks/Boxed Warnings	QT Risk	CNS Penetration	Regional Availability Notes
Metoclopramide	D2 antagonist; 5-HT4 agonist	10 mg PO before meals and HS; IV 10 mg PRN	Gastroparesis, NV, GERD adjunct	Tardive dyskinesia risk; limit to ≤12 weeks	Low–moderate	Yes	Widely available
Domperidone	Peripheral D2 antagonist	10 mg PO TID before meals	Gastroparesis, NV	QT prolongation/arrhythmia	Moderate	Minimal	Not FDA-approved; available in many countries/IND
Prucalopride	Selective 5-HT4 agonist	2 mg PO daily; 1 mg if severe renal	Chronic idiopathic constipation	Headache/diarrhea; rare mood effects	Low	Minimal	US/EU and others
Tegaserod	Partial 5-HT4 agonist	6 mg PO BID before meals	IBS-C (women <65, low CV risk)	CV ischemia risk; restricted use	Possible	Minimal	Reintroduced with restrictions (some regions)
Erythromycin	Motilin receptor agonist	125–250 mg PO TID; IV 3 mg/kg q8h	Short-course gastroparesis, inpatient prokinetic	QT/proarrhythmia; drug interactions; tachyphylaxis	Moderate	Minimal	Off-label prokinetic use
Neostigmine	AChE inhibitor	2 mg IV over 3–5 min	Acute colonic pseudo-obstruction	Bradycardia/bronchospasm; give with monitoring	No	N/A	Inpatient only
Cisapride	5-HT4 agonist	5–10 mg QID	Refractory gastroparesis/GERD	Torsades de pointes; restricted/withdrawn	High	Minimal	Restricted access programs
Mosapride	5-HT4 agonist	5 mg PO TID	Functional dyspepsia/gastroparesis	QT risk with interactions	Low–moderate	Minimal	Asia/other regions
Itopride	D2 antagonist + AChE inhibitor	50 mg PO TID	Functional dyspepsia/gastroparesis	Generally well tolerated	Low	Minimal	Asia/other regions

Comparison Table 2 — Motility-Promoting Options for Constipation (Adjacency for Clinical Choice)

Class	Agent	Mechanism	Typical Dose	Use Case	Key Advantages	Key Cautions
5-HT4 agonist	Prucalopride	Enteric 5-HT4 stimulation → ↑ colonic transit	2 mg QD (1 mg if severe renal)	Chronic idiopathic constipation	Works when laxatives fail; once daily	Headache/diarrhea early; avoid in obstruction
Secretagogue	Linaclotide	GC-C agonist → ↑ cGMP, Cl-/HCO3- secretion	145 mcg QD (IBS-C 290 mcg)	CIC, IBS-C	Softens stool, ↓ pain in IBS-C	Diarrhea; empty stomach dosing
Secretagogue	Plecanatide	GC-C agonist	3 mg QD	CIC, IBS-C	Similar to linaclotide; well tolerated	Diarrhea risk
Secretagogue	Lubiprostone	ClC-2 activator	24 mcg BID (CIC)	CIC, OIC (lower dose for IBS-C)	Useful in OIC; minimal systemic absorption	Nausea; pregnancy caution
PAMORA	Naloxegol	Peripheral μ-antagonist	25 mg QD	Opioid-induced constipation	Reverses opioid gut effects	Avoid with strong CYP3A4 inhibitors
PAMORA	Methylnaltrexone	Peripheral μ-antagonist	Weight-based SC or PO	OIC (palliative, chronic)	Rapid onset SC	Abdominal pain; avoid obstruction
PAMORA	Naldemedine	Peripheral μ-antagonist	0.2 mg QD	OIC (non-cancer)	Oral, once daily	CYP3A interactions