GI motility + secretion

Category: signaling

Overview

Gut motility + secretion under multiple receptor controls. μ-opioid receptors on enteric neurons slow transit (constipating side effect of opioids; therapeutic for diarrhea via loperamide which is P-gp-extruded from brain). 5HT3 antagonism slows motility + reduces secretion; 5HT4 agonism (prucalopride — not in registry) increases motility. CFTR + guanylate cyclase C activators (lubiprostone — ClC-2; linaclotide + plecanatide — GC-C) increase intestinal chloride/water secretion → laxation. Osmotic laxatives (PEG, lactulose) draw water in by oncotic gradient. Bulk laxatives (psyllium not in registry). Antispasmodics (dicyclomine, hyoscyamine — anticholinergic) reduce smooth-muscle tone. Anti-emetics covered in serotonin (5-HT3) + dopamine (D2) pathways.

Organ Systems

• digestive

Pathway Steps

1. gut-receptor-stimulation → gi-motility-or-secretion — via multiple receptors converge on neuronal + smooth-muscle + epithelial outputs. GI motility and secretion are controlled by the enteric nervous system via receptors for ACh (M3), serotonin (5-HT4 prokinetic), motilin, and others. Drugs target these — prokinetics (metoclopramide, prucalopride) stimulate motility, antisecretory and antispasmodic agents reduce it — for conditions from gastroparesis to IBS.

Known Modulators

• loperamide (activator) — μ-opioid receptor (gut-restricted via P-gp efflux). OTC antidiarrheal; P-gp efflux at BBB → minimal CNS opioid effect at therapeutic doses; abuse case reports at supra-therapeutic doses (cardiotoxicity)
• diphenoxylate atropine (activator) — μ-opioid + muscarinic antagonist (combo). Lomotil; atropine sub-therapeutic dose discourages abuse; controlled-substance schedule V
• eluxadoline (activator) — μ-opioid agonist + δ-opioid antagonist (gut-restricted). IBS-D; minimal systemic absorption; pancreatitis risk in cholecystectomized patients (boxed warning)
• lubiprostone (activator) — ClC-2 chloride channels (intestinal apical). chronic idiopathic constipation + IBS-C; opioid-induced constipation; minimal systemic absorption
• linaclotide (activator) — guanylate cyclase-C (GC-C). IBS-C + CIC; raises intestinal cGMP → CFTR activation + visceral analgesia; gut-restricted (minimal systemic exposure)
• polyethylene glycol (activator) — osmotic laxative (no receptor target). PEG 3350 (MiraLAX); inert polymer; binds water + transit unchanged through gut; chronic use safe; colonoscopy prep at higher volumes
• lactulose (activator) — osmotic + colonic bacterial metabolism (NH3 trap). osmotic laxative + hepatic encephalopathy (bacterial conversion to lactate + acetate traps NH4+); flatulence from gas production
• docusate (activator) — surfactant stool softener (mechanism debated). sodium docusate; widely used despite weak evidence for chronic constipation
• orlistat (inhibitor) — pancreatic + gastric lipase (gut-restricted). Xenical/Alli; reduces dietary fat absorption ~30%; steatorrhea + flatulence; fat-soluble vitamin malabsorption
• simethicone (activator) — surface tension reducer (no receptor). OTC anti-gas; coalesces small bubbles; pk_unauthored:local-acting (zero systemic absorption)
• acarbose (inhibitor) — α-glucosidase (gut-restricted). T2DM; delays carbohydrate absorption → blunts postprandial glucose excursion; flatulence + diarrhea common
• pancrelipase (activator) — exocrine pancreatic enzyme replacement (lipase + protease + amylase). CF + chronic pancreatitis; enzyme-replacement therapy taken with meals; enteric-coated to survive gastric acid
• aprepitant (inhibitor) — NK1 receptor (substance P). chemo-induced N/V; component of triple antiemetic (5HT3-i + dex + aprepitant); CYP3A4 substrate + inhibitor + inducer authored Wave 2a v1.1
• palonosetron (inhibitor) — 5-HT3 (long-acting). long-acting setron; chemo N/V; minimal QT effect vs ondansetron

References

• PMID 33989661