Lower GI Pharmacology: Constipation, Diarrhea, CDI, and IBS
Laxatives · PAMORAs · Antidiarrheals · CDI treatment · IBS drug classes
Laxative Classes and Mechanisms
| Class |
Mechanism |
Agents / Onset |
Key Caution |
| Osmotic |
Retains water in lumen by osmotic pressure |
Polyethylene glycol (preferred); lactulose; magnesium salts. Onset 24–48 h |
Magnesium salts: avoid in renal impairment |
| Stimulant |
Stimulates myenteric plexus; inhibits colonic fluid absorption |
Senna; bisacodyl. Onset 6–12 h oral |
Safe long-term; cathartic colon concern not substantiated |
| Secretagogue |
Activates ClC-2 channels (lubiprostone) or GC-C (linaclotide/plecanatide) → chloride/water secretion |
Lubiprostone; linaclotide; plecanatide; tenapanor |
GC-C agonists: black box warning — do not use under age 2 |
| PAMORA |
Blocks peripheral mu-opioid receptors in ENS without crossing blood-brain barrier |
Methylnaltrexone (SC); naloxegol; naldemedine (oral) |
Contraindicated in GI obstruction; naloxegol: CYP3A4 substrate |
Clostridioides difficile Infection Treatment Hierarchy
Non-Severe CDI
Fidaxomicin Preferred
- Fidaxomicin 200 mg twice daily x 10 days (preferred): narrower spectrum, ~40% lower recurrence than vancomycin for non-hypervirulent strains
- Vancomycin 125 mg four times daily x 10 days: acceptable alternative
- Metronidazole: no longer first-line; inferior cure and recurrence rates
Severe / Fulminant CDI
Vancomycin ± IV Metronidazole
- Severe (WBC ≥15,000 or Cr ≥1.5): vancomycin 125 mg four times daily
- Fulminant (hypotension, ileus, megacolon): vancomycin 500 mg four times daily (oral/NG) + IV metronidazole 500 mg every 8 hours
- Fulminant: immediate surgical consultation
Recurrent CDI
FMT or Pulsed Vancomycin
- First recurrence: fidaxomicin (if prior vancomycin) or vancomycin
- 2nd+ recurrence: FMT (80–90% resolution) or extended pulsed-tapered vancomycin
- Bezlotoxumab: single IV infusion during antibiotic course; reduces recurrence ~10 pp in high-risk patients; black box warning for heart failure
IBS Pharmacotherapy: Subtype-Driven Selection
IBS-C
Increase Secretion and Transit
- Linaclotide 290 mcg daily: GC-C agonist; reduces pain via luminal cyclic GMP on nociceptors
- Plecanatide 3 mg daily: GC-C agonist; pH-activated proximally
- Tenapanor 50 mg twice daily: NHE3 inhibitor
- Lubiprostone 8 mcg twice daily: ClC-2 activator
IBS-D and Visceral Pain
Slow Transit and Reduce Hypersensitivity
- Alosetron: 5-HT3 antagonist; women with severe IBS-D only; REMS required; risk of ischemic colitis
- Eluxadoline: mu/kappa agonist + delta antagonist; CI post-cholecystectomy (pancreatitis)
- Rifaximin 550 mg three times daily x 14 days: targets dysbiosis; retreatable
- Low-dose TCA (amitriptyline/nortriptyline): visceral pain modulation + slows transit; first-line neuromodulator
Critical Rule — Eluxadoline
Eluxadoline is absolutely contraindicated in patients without a gallbladder. Mu-opioid receptor agonism causes sphincter of Oddi spasm and acute pancreatitis in post-cholecystectomy patients. Always check surgical history before prescribing.