Step 1 · Gastrointestinal

Liver & Functional Bowel Pharmacology

Name: Liver & Functional Bowel Pharmacology
Creator: Veli Bakalov, MD

Portal pressure, ammonia and gut secretion: the receptors behind liver and bowel drugs

Gastrointestinal·Pharmacology·6 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Nonselective β-blockers lower portal pressure through β1 blockade (↓cardiac output) plus β2 blockade that leaves α1 splanchnic vasoconstriction unopposed; β1-selective metoprolol and atenolol do not work.
Carvedilol adds α1 blockade and lowers HVPG most; NSBBs are for prophylaxis (with band ligation after a bleed), not for the actively bleeding, hypotensive patient.
Vasopressin and terlipressin constrict splanchnic arterioles through V1 (Gq → IP3/Ca2+) and cause ischemia and hyponatremia; octreotide (somatostatin analog) is the first-line vasoactive drug and causes gallstones.
Lactulose is fermented to acids that convert NH3 to trapped NH4+ and purge it; titrate to 2–3 soft stools and correct precipitants such as bleeding, infection, sedatives and hypokalemia.
Rifaximin is a minimally absorbed rifamycin (RNA polymerase inhibitor) added to lactulose for recurrent hepatic encephalopathy; it also treats IBS-D and noninvasive travelers' diarrhea.
Linaclotide and plecanatide activate guanylate cyclase-C → cGMP → CFTR chloride secretion (same receptor as E. coli heat-stable toxin); lubiprostone activates ClC-2 and causes nausea.
Alosetron (5-HT3 antagonist) is restricted to women with severe IBS-D because of ischemic colitis; eluxadoline (μ-agonist) causes pancreatitis and is contraindicated after cholecystectomy.
Dicyclomine and hyoscyamine are antimuscarinic antispasmodics; avoid in angle-closure glaucoma, urinary retention and the frail elderly.
Methylnaltrexone (quaternary amine) and naloxegol block gut μ receptors without reversing analgesia; alvimopan shortens postoperative ileus, capped at 15 doses because of MI risk.

Lowering portal pressure

Nonselective β-blockers (NSBBs). Propranolol, nadolol and carvedilol cut portal venous inflow two ways. β1 blockade slows the heart and lowers cardiac output; β2 blockade removes splanchnic arteriolar vasodilation, leaving α1-adrenergic constriction of mesenteric inflow unopposed. Portal flow and the hepatic venous pressure gradient (HVPG) fall, reducing variceal wall tension.

Use. NSBBs provide primary prophylaxis for medium or large varices and, with band ligation, prevent rebleeding. Propranolol and nadolol are titrated to a resting heart rate of about 55–60 bpm or the maximum tolerated dose. Carvedilol also blocks α1 receptors, lowering intrahepatic resistance, and gives the largest HVPG fall; nadolol is hydrophilic and renally cleared. Watch for bradycardia, hypotension and bronchospasm. NSBBs are held while a patient is actively bleeding and hypotensive.

β1-selective metoprolol and atenolol do not lower portal pressure: the β2 component is what unmasks splanchnic vasoconstriction.

Vasopressin and terlipressin. These act on Gq-coupled V1 receptors of vascular smooth muscle (IP₃ → Ca²⁺), constricting splanchnic arterioles during acute variceal bleeding; terlipressin is the longer-acting analog. Toxicity is ischemic (myocardial, mesenteric, digital, skin), and V2 activity (Gs → cAMP → aquaporin-2) adds hyponatremia. Terlipressin also treats hepatorenal syndrome, where fluid overload and respiratory failure are its main risks.

Octreotide. This somatostatin analog (mainly SSTR2) blocks release of vasodilatory peptides such as glucagon and VIP, producing splanchnic vasoconstriction. It is started as soon as variceal bleeding is suspected, with IV ceftriaxone, ahead of band ligation within 12 hours, and continued 2–5 days. By inhibiting CCK-driven gallbladder contraction it causes gallstones and sludge; steatorrhea, nausea, hypo- or hyperglycemia and bradycardia also occur. It also treats acromegaly, carcinoid syndrome and VIPoma.

Drugs that lower portal pressure

Drug	Mechanism	Role	Key toxicity
Propranolol, nadolol	β1 + β2 blockade	Primary and secondary prophylaxis	Bradycardia, bronchospasm
Carvedilol	β1 + β2 + α1 blockade	Prophylaxis; largest HVPG fall	Hypotension
Vasopressin, terlipressin	V1 (Gq) vasoconstriction	Acute bleeding; hepatorenal syndrome	Ischemia, hyponatremia
Octreotide	↓Glucagon and VIP release	First-line for acute bleeding	Gallstones, steatorrhea

Hepatic encephalopathy

Lactulose. Gut-derived ammonia normally cleared by the hepatic urea cycle reaches the brain in cirrhosis, where astrocytes convert it to glutamine and swell. Lactulose lowers it inside the colon:

Arrives intactNo brush-border enzyme splits this synthetic disaccharide.
Bacterial fermentationLactic, acetic and other short-chain fatty acids form.
pH fallsNH₃ + H⁺ → NH₄⁺, which cannot diffuse back into blood; acidity favors non-urease-producing flora.
Osmotic catharsisTrapped ammonium leaves in the stool.

Using it. Lactulose is first-line for overt encephalopathy and for preventing recurrence, titrated to 2–3 soft stools a day. Overuse causes diarrhea, dehydration, hypernatremia and hypokalemia, which can worsen encephalopathy. Precipitants are always corrected: GI bleeding, infection including spontaneous bacterial peritonitis, constipation, sedatives, hypokalemia and alkalosis.

Hypokalemia increases renal ammonia production, and alkalosis converts NH₄⁺ to lipid-soluble NH₃ that crosses the blood-brain barrier, so potassium is replaced.

Rifaximin. This rifamycin is minimally absorbed (<1%) and inhibits the β subunit of bacterial DNA-dependent RNA polymerase, reducing ammonia-producing flora. Added to lactulose, it lowers recurrence of overt encephalopathy and hospitalizations, with few systemic effects or drug interactions. It also treats travelers' diarrhea from noninvasive E. coli and IBS-D (a 14-day course that may be repeated). Older options are more toxic: neomycin (30S inhibitor; oto- and nephrotoxic) and metronidazole (neuropathy).

Secretagogues for constipation and IBS-C

Guanylate cyclase-C agonists. Linaclotide and plecanatide mimic guanylin and uroguanylin. Binding apical guanylate cyclase-C raises cGMP, which activates protein kinase G II to phosphorylate CFTR; Cl⁻ and HCO₃⁻ are secreted, Na⁺ and water follow, and stool softens and moves faster. Extracellular cGMP also dampens visceral pain afferents. Both treat IBS-C and chronic idiopathic constipation; diarrhea is the main adverse effect, and they are avoided in young children because of severe dehydration.

E. coli heat-stable toxin (ST) causes secretory diarrhea through the same receptor; cholera toxin and heat-labile toxin raise cAMP through Gs instead.

Lubiprostone. A prostaglandin E1–derived bicyclic fatty acid, it activates apical type-2 chloride channels (ClC-2), producing chloride-rich secretion independent of GC-C and cGMP. It is approved for chronic idiopathic constipation, IBS-C in women and opioid-induced constipation. Nausea is classic (take with food); diarrhea and headache also occur. Secretagogues add water, not propulsion; prucalopride (5-HT₄ agonist) is the prokinetic alternative.

IBS-D and cramping pain

Alosetron. A selective 5-HT₃ antagonist that slows colonic transit and reduces secretion and visceral pain. It is restricted to women with severe IBS-D refractory to conventional therapy, carries a boxed warning for ischemic colitis and serious complications of constipation, and is stopped at once for rectal bleeding or bloody diarrhea.

Eluxadoline. A locally acting mixed opioid ligand (μ- and κ-agonist, δ-antagonist) that slows transit and secretion. Constipation and nausea are common, and it is Schedule IV.

Eluxadoline can trigger sphincter of Oddi spasm and pancreatitis; it is contraindicated after cholecystectomy and with heavy alcohol use, prior pancreatitis, biliary obstruction or severe hepatic impairment.

Loperamide. The over-the-counter μ-agonist for diarrhea; P-glycoprotein keeps it out of the CNS, but megadoses prolong QT and cause torsades.

Antispasmodics. Dicyclomine and hyoscyamine (the active levo-isomer of atropine) block M3 receptors on intestinal smooth muscle, easing spasm and postprandial cramping in either subtype. Anticholinergic effects include dry mouth, blurred vision, urinary retention, constipation, tachycardia and confusion in the elderly; avoid in angle-closure glaucoma, urinary obstruction, myasthenia gravis and GI obstruction.

Functional bowel drugs

Drug	Target	Use	Signature adverse effect
Linaclotide, plecanatide	GC-C → cGMP → CFTR	IBS-C, chronic constipation	Diarrhea
Lubiprostone	ClC-2 activator	Constipation, IBS-C, opioid constipation	Nausea
Alosetron	5-HT₃ antagonist	Severe IBS-D in women	Ischemic colitis
Eluxadoline	μ/κ agonist, δ antagonist	IBS-D	Pancreatitis
Dicyclomine, hyoscyamine	M3 antagonist	Cramping pain	Anticholinergic effects

Opioid-induced constipation and postoperative ileus

Mechanism. μ receptors in the myenteric plexus reduce acetylcholine release, suppressing propulsion while increasing segmental contraction and sphincter tone; fluid absorption rises. No tolerance develops, so laxatives accompany chronic opioids.

Peripherally acting μ-antagonists (PAMORAs). Methylnaltrexone (subcutaneous or oral) is a quaternary amine whose permanent charge excludes it from the CNS. Naloxegol is an oral PEGylated naloxone kept out of the brain by P-glycoprotein; as a CYP3A4 substrate it is not combined with strong inhibitors such as clarithromycin or ketoconazole. Both block gut μ receptors while preserving analgesia and avoiding withdrawal.

PAMORAs are contraindicated in known or suspected bowel obstruction because of perforation risk.

Alvimopan. This oral PAMORA shortens postoperative ileus after partial bowel resection with primary anastomosis. A myocardial infarction signal with long-term use limits it to a hospital-only program of at most 15 doses, and it is not given after more than 7 consecutive days of therapeutic opioids.