GI Pharmacology · Module 5 of 8

Lower GI Pharmacology: Constipation, Diarrhea, and IBS

Laxatives · PAMORAs · Antidiarrheals · CDI · IBS pharmacotherapy

Four laxative classes by mechanism: osmotic (PEG 3350 preferred — negligible absorption, no electrolyte shifts, safe in renal disease; lactulose — bloating from fermentation; magnesium salts — avoid in renal impairment); stimulant (senna, bisacodyl — myenteric plexus stimulation + reduced absorption, onset 6–12 hours, safe long-term); secretagogue (lubiprostone — Cl⁻ channel; linaclotide/plecanatide — GC-C agonists, also analgesic via cGMP on submucosal nociceptors); bulk-forming (psyllium — adequate fluid required, beware obstruction).
PAMORAs (methylnaltrexone, naloxegol, naldemedine) block enteric mu-opioid receptors without crossing the blood-brain barrier — reverse OIC within 24–48 hours without compromising analgesia; mechanism of peripheral selectivity: methylnaltrexone (quaternary ammonium charge), naloxegol (P-gp substrate at BBB), naldemedine (bulky side chain); contraindicated in GI obstruction; naloxegol is a CYP3A4 substrate — strong CYP3A4 inhibitors contraindicated.
Loperamide (mu-opioid agonist in myenteric plexus, P-gp substrate at BBB → no CNS effects at therapeutic doses): first-line for non-inflammatory acute and chronic functional diarrhea; contraindicated in CDI, dysenteric presentations (blood/fever), and acute severe UC flare (toxic megacolon risk); supratherapeutic doses saturate P-gp → QTc prolongation, ventricular tachycardia. Bismuth subsalicylate: avoid in children/adolescents with viral illness (Reye syndrome); salicylate absorbed — warfarin interaction. Cholestyramine for bile acid diarrhea: separates all co-medications by 1–2 hours (binds thyroxine, warfarin, digoxin, fat-soluble vitamins).
CDI treatment hierarchy (fidaxomicin now preferred over vancomycin for non-severe): non-severe — fidaxomicin 200 mg BID ×10 days (lower recurrence, narrower spectrum, spares colonization-resistance organisms) OR vancomycin 125 mg QID ×10 days; severe (WBC ≥15k or Cr ≥1.5) — vancomycin; fulminant — vancomycin 500 mg QID + IV metronidazole + surgical consult; metronidazole downgraded to last resort only; recurrent CDI — fidaxomicin > vancomycin for first recurrence; FMT for second or subsequent recurrences (FDA-approved products: Rebyota, Vowst); bezlotoxumab (anti-toxin B, single IV dose) for high-risk patients.
IBS-C: linaclotide/plecanatide (GC-C agonists, FDA black box: contraindicated <2 years; primary AE is diarrhea); tenapanor (NHE3 inhibitor); lubiprostone. IBS-D: alosetron (5-HT3 antagonist, REMS required, women only, stop if constipation or rectal bleeding); eluxadoline (mixed μ/κ agonist/δ antagonist — absolutely contraindicated post-cholecystectomy: sphincter of Oddi spasm → pancreatitis; also contraindicated with alcohol use disorder); rifaximin 550 mg TID ×14 days (retreatable). Both subtypes: low-dose TCAs (visceral hypersensitivity — not antidepressant dose; slow transit a benefit in IBS-D).

BBB = blood-brain barrier · BID = twice daily · cGMP = cyclic guanosine monophosphate · CDI = Clostridioides difficile infection · CYP3A4 = cytochrome P450 3A4 · FMT = fecal microbiota transplant · GC-C = guanylate cyclase-C · IBS-C = irritable bowel syndrome with predominant constipation · IBS-D = irritable bowel syndrome with predominant diarrhea · NHE3 = sodium-hydrogen exchanger isoform 3 · OIC = opioid-induced constipation · PAMORA = peripherally acting mu-opioid receptor antagonist · PEG = polyethylene glycol · P-gp = P-glycoprotein · QID = four times daily · REMS = Risk Evaluation and Mitigation Strategy · TCA = tricyclic antidepressant · UC = ulcerative colitis

Laxative Classes

Class	Mechanism	Key Agents	Clinical Notes
Osmotic	Retain water in lumen via osmotic pressure	PEG 3350 (preferred); lactulose; magnesium hydroxide/citrate	PEG: negligible absorption, no electrolyte shifts, safe in renal impairment — first-line for chronic constipation; magnesium: avoid in severe renal impairment; lactulose: fermentation → bloating
Stimulant	Stimulate myenteric plexus; inhibit colonic fluid absorption	Senna (prodrug activated by colonic bacteria); bisacodyl (esterase activation in intestinal wall)	Onset 6–12 hours oral; safe for long-term use (cathartic colon concern not supported by prospective data)
Secretagogue	Activate apical epithelial channels → Cl⁻ and water secretion	Lubiprostone (ClC-2 channel); linaclotide, plecanatide (GC-C agonists → cGMP)	GC-C agonists: FDA black box — contraindicated under age 2 (severe dehydrating diarrhea); cGMP also inhibits submucosal nociceptors → analgesic benefit independent of laxative effect
Bulk-forming	Absorb water, expand stool bulk, stimulate peristalsis	Psyllium; methylcellulose	Must be taken with adequate fluid to prevent esophageal/intestinal obstruction; onset 1–3 days

PAMORAs — Opioid-Induced Constipation

Methylnaltrexone

Quaternary Ammonium Charge

Permanent positive charge → substantially limits CNS penetration
SC injection: rapid onset within 4 hours; useful for acute OIC in hospitalized/palliative patients
Does not reverse central analgesia

Naloxegol

PEG Conjugate / P-gp Substrate

PEG conjugation makes it a P-gp substrate at BBB → CNS exposure <1% of plasma
Oral once daily; approved for non-cancer OIC
CYP3A4 substrate: strong inhibitors contraindicated; moderate inhibitors require dose reduction

Naldemedine

Bulky Side Chain

Bulky side chain reduces BBB penetration
Oral once daily; approved for non-cancer OIC
All three PAMORAs: contraindicated in known/suspected GI obstruction; reverse OIC within 24–48 hours

Antidiarrheal Agents

Loperamide

Peripheral Mu-Opioid Agonist

Potent mu-opioid agonist in myenteric plexus → reduces propulsive peristalsis, increases segmental contractions, reduces secretion, increases anal sphincter tone
P-gp substrate at BBB → negligible CNS entry at therapeutic doses; no analgesia or dependence
Contraindicated: CDI (toxic megacolon); dysenteric diarrhea with blood/fever; acute severe UC flare
Supratherapeutic doses saturate P-gp → QTc prolongation, ventricular tachycardia

Bismuth Subsalicylate

Traveler's Diarrhea

Antimicrobial (bismuth), anti-secretory (salicylate inhibits prostaglandin synthesis), toxin binding
Effective for traveler's diarrhea prophylaxis and treatment
Avoid in children/adolescents with viral illness (Reye syndrome — systemic salicylate absorption)
Warfarin interaction (salicylate); black stool/tongue from bismuth sulfide — warn patients

Rifaximin / Cholestyramine

Targeted Antimicrobial / Bile Acid Binder

Rifaximin: minimally absorbed (<0.4%) rifamycin; high intraluminal concentrations; traveler's diarrhea from non-invasive enterotoxigenic E. coli; not for invasive pathogens
Cholestyramine: bile acid sequestrant; effective for bile acid diarrhea (post-ileal resection, post-cholecystectomy)
Cholestyramine binds co-medications in lumen: thyroxine, warfarin, digoxin, fat-soluble vitamins; separate all other drugs by ≥1–2 hours

Clostridioides difficile Infection — Severity-Based Treatment

Severity	Definition	First-Line Treatment	Notes
Non-severe	WBC <15,000; Cr <1.5 mg/dL	Fidaxomicin 200 mg BID ×10 days (preferred) OR vancomycin 125 mg QID ×10 days	Fidaxomicin: similar cure rates, ~40% lower recurrence; spares colonization-resistance organisms
Severe	WBC ≥15,000 OR Cr ≥1.5 mg/dL	Vancomycin 125 mg QID ×10 days	Data favor vancomycin over fidaxomicin for severe disease
Fulminant	Hypotension, ileus, or toxic megacolon	Vancomycin 500 mg QID oral/NG + IV metronidazole 500 mg q8h + surgical consult	IV metronidazole reaches colon via luminal secretion when ileus prevents oral drug distribution
Recurrent	First: fidaxomicin preferred (if prior treatment was vancomycin); ≥2nd: FMT or extended pulsed-tapered vancomycin	FMT: 80–90% resolution for multiply recurrent CDI (FDA-approved: Rebyota rectal; Vowst oral capsules)	Bezlotoxumab (anti-toxin B, single IV infusion) for high-risk patients during antibiotic treatment; black box: heart failure exacerbation

IBS Pharmacotherapy — Subtype-Driven

IBS-C: Constipation-Predominant

Secretagogues and NHE3 Inhibitor

Linaclotide 290 mcg daily (GC-C agonist): increases intraluminal cGMP → CFTR activation → Cl⁻ and HCO₃⁻ secretion + accelerated transit; luminal cGMP inhibits pain-sensing neurons → analgesic benefit independent of laxative effect
Plecanatide 3 mg daily (GC-C agonist): pH-activated in proximal intestine; similar mechanism
Tenapanor 50 mg BID (NHE3 inhibitor): reduces Na⁺ and water absorption from intestinal lumen; also approved for hyperphosphatemia in dialysis patients
Lubiprostone 8 mcg BID (ClC-2 channel)
Linaclotide and plecanatide: FDA black box — absolutely contraindicated <2 years (risk of severe dehydrating diarrhea from CFTR activation in immature GI physiology); primary AE is diarrhea

IBS-D: Diarrhea-Predominant

Key Contraindications to Know

Alosetron (5-HT3 antagonist): slows colonic transit + reduces visceral afferent signaling; approved for women with severe IBS-D unresponsive to conventional therapy only; REMS program required (ischemic colitis and severe constipation risk); stop immediately if constipation or rectal bleeding develops
Eluxadoline (μ/κ agonist + δ antagonist): absolutely contraindicated post-cholecystectomy — unopposed μ agonism at sphincter of Oddi → spasm → acute pancreatitis; also contraindicated with alcohol use disorder or >3 drinks/day
Rifaximin 550 mg TID ×14 days: targets dysbiosis; retreatable on relapse with similar efficacy
Low-dose TCAs (amitriptyline/nortriptyline 10–50 mg at bedtime): visceral hypersensitivity mechanism (Na⁺ channel block on sensory neurons); anticholinergic slowing of transit is a therapeutic benefit in IBS-D; NNT ~4–5

Critical Rules — CDI and IBS High-Risk Contraindications

CDI: metronidazole is no longer first-line for any severity category (IDSA/SHEA 2017 guidelines). Loperamide is absolutely contraindicated in CDI — it inhibits motility needed for toxin clearance and dramatically increases risk of toxic megacolon. CDI must be excluded before initiating antidiarrheal therapy in antibiotic-associated or hospital-acquired diarrhea.

IBS-D: eluxadoline in post-cholecystectomy patients is an absolute contraindication — sphincter of Oddi spasm causes acute pancreatitis because there is no gallbladder to buffer biliary pressure. Always ask about prior cholecystectomy before prescribing. Alosetron requires the patient to be enrolled in the REMS program and only prescribers enrolled in the program may dispense it; stop at first sign of constipation or rectal bleeding (ischemic colitis).

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter on Gastrointestinal Pharmacology	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
Chey WD et al.	Naloxegol for opioid-induced constipation in patients with noncancer pain	N Engl J Med. 2014;370(25):2387–2396
Awouters F et al.	Loperamide: survey of studies on mechanism of its antidiarrheal activity	Dig Dis Sci. 1993;38(6):977–995
McDonald LC et al.	Clinical practice guidelines for Clostridioides difficile infection: 2017 IDSA/SHEA update	Clin Infect Dis. 2018;66(7):e1–e48
Louie TJ et al.	Fidaxomicin versus vancomycin for Clostridioides difficile infection	N Engl J Med. 2011;364(5):422–431
Wilcox MH et al.	Bezlotoxumab for prevention of recurrent Clostridioides difficile infection (MODIFY trials)	N Engl J Med. 2017;376(4):305–317
van Nood E et al.	Duodenal infusion of donor feces for recurrent Clostridioides difficile	N Engl J Med. 2013;368(5):407–415
Rao S et al.	A 12-week randomized controlled trial evaluating linaclotide in irritable bowel syndrome with constipation	Am J Gastroenterol. 2012;107(11):1714–1724
Chang L et al.	Incidence of ischemic colitis and serious complications of constipation with alosetron	Am J Gastroenterol. 2006;101(5):1069–1079
Ford AC et al.	Effect of antidepressants and psychological therapies in irritable bowel syndrome: updated meta-analysis	Am J Gastroenterol. 2019;114(1):21–39
Pimentel M et al.	Rifaximin therapy for patients with irritable bowel syndrome without constipation (TARGET trials)	N Engl J Med. 2011;364(1):22–32