Clinical meaning
Advanced IBS pharmacotherapy requires subtype-specific prescribing guided by the predominant bowel pattern (IBS-C, IBS-D, IBS-M) and the primary symptom driver (pain, diarrhea, constipation, bloating). The gut-brain axis is the therapeutic target: visceral hypersensitivity (augmented afferent pain signaling from the gut via dorsal horn neurons to the brain), dysmotility (serotonin-mediated — 95% of body serotonin is in the GI tract), altered intestinal secretion, and microbiome dysbiosis each respond to different pharmacological mechanisms. IBS-C agents: linaclotide and plecanatide are guanylate cyclase-C (GC-C) agonists that increase intraluminal cGMP, stimulating chloride/bicarbonate secretion and accelerating transit while simultaneously reducing visceral pain through extracellular cGMP — this dual mechanism is unique and advantageous. Lubiprostone activates type-2 chloride channels (ClC-2) on apical enterocyte membranes, increasing chloride-rich fluid secretion. Tegaserod (5-HT4 agonist) enhances peristalsis but is restricted to women <65 without cardiovascular risk. IBS-D agents: eluxadoline is a mixed mu-opioid receptor agonist / delta-opioid antagonist / kappa-opioid agonist — it slows motility without complete constipation (unlike loperamide). Rifaximin (non-absorbable antibiotic) modifies the gut microbiome and reduces bacterial gas production. Alosetron (5-HT3 antagonist) is highly effective but restricted to severe IBS-D in women due to ischemic colitis risk. Bile acid sequestrants (cholestyramine) benefit the 25-50% of IBS-D patients with bile acid malabsorption (can be diagnosed with SeHCAT scan or empiric trial). Pain-directed therapy: low-dose TCAs (amitriptyline 10-25 mg) modulate visceral pain via descending inhibitory pain pathways and slow transit (favor IBS-D); SSRIs/SNRIs accelerate transit (favor IBS-C) and address comorbid anxiety/depression. Antispasmodics (dicyclomine, hyoscyamine) provide PRN relief of cramping.