Antidiarrheal Agents

Diarrhea is defined as “the too rapid evacuation of too ______ stools.”

fluid

Stool weight is largely determined by ______ content.

water

A stool water weight above ______ g/day is abnormal.

200

Diarrhea can result from increased ______ load within the intestine.

osmotic

Excessive secretion of ______ and ______ into the lumen can cause diarrhea.

electrolytes, water

Diarrhea may result from ______ of protein and fluid from the mucosa.

exudation

Altered intestinal ______ causes rapid transit and decreased fluid absorption.

motility

Most cases involve multiple processes, leading to increased stool ______ and ______ content.

volume, water

Diarrhea is a ______, not a disease—treat the underlying problem first.

symptom

Osmotic diarrhea in lactose-intolerant patients improves when ______ is avoided.

lactose

Pancreatic insufficiency causing malabsorption can be treated with ______.

pancreatic enzymes

Secretory diarrhea caused by tumors may require treatment of the ______-secreting tumor.

hormone

Acute diarrhea is most often ______ in nature and usually self-limiting.

infectious

Antidiarrheals may worsen infections by delaying clearance of invasive organisms such as ______.

E. coli O157:H7/bacteria/viruses

In both acute and chronic diarrhea, replenishment of ______ and ______ is essential.

fluids, electrolytes

Chronic diarrhea is common in AIDS, affecting –% of patients.

50,90

The most important step in treating chronic diarrhea is to identify the underlying ______.

cause

In acute infectious diarrhea (especially from invasive organisms), antidiarrheals can be dangerous because they:

• mask symptoms

• delay clearance of bacteria

• increase the risk of the infection spreading into the body

Only use drugs if diarrhea is severe/persistent, and never in acute invasive infections.

Many antidiarrheal drugs act by decreasing intestinal ______.

motility

In suspected or proven enterohemorrhagic E. coli, ______ should be avoided due to risk of HUS.

antibiotics

If a patient has enterohemorrhagic E. coli (EHEC), you should not give antibiotics.

• E. coli release more Shiga toxin.

• Shiga toxin damages the intestinal lining, leading to bloody diarrhea.

• It can also be absorbed into the blood and travel to the kidneys.

• hemolytic uremic syndrome (HUS) —> blood clots form in the kidney vessels —> acute kidney injury

Traveler’s Diarrhea (TD) = watery or soft stools + other symptoms like:

• fecal urgency

• abdominal cramps

• nausea

• vomiting

• or fever

TD is grouped into 3 levels:

• Mild: tolerable, not distressing, doesn’t interfere with plans.

• Intermediate: distressing and does interfere with plans or function.

• Severe: completely incapacitating, can’t do planned activities.

Most cases resolve in ~4 days, but some last up to 2 weeks.

Bismuth Subsalicylate - MOA

• bismuth + salicylate in a clay mixture

• in the stomach’s low pH, it forms bismuth oxychloride + salicylic acid

• salicylic acid —> anti-inflammatory effect

• bismuth —> not absorbed, passes through GI, may have anti-secretory and antimicrobial activity

Bismuth Subsalicylate - Adverse Effects

• very few

• overdose can cause salicylate toxicity

• bacteria turn bismuth into bismuth sulfide, which can make the stool and tongue black

Younger patients (especially children and teenagers) should not take bismuth subsalicylate because the salicylatecomponent acts like aspirin (acetylsalicylic acid).

• Salicylates are linked to Reye’s syndrome, a rare but serious condition that causes:

  • Brain swelling (encephalopathy)

  • Liver damage (fatty degeneration)

• Reye’s syndrome usually occurs after a viral illness. Bismuth subsalicylate is contradicted in younger patients recovering from viral infections.

Probiotics

• When the normal gut microflora balance is disturbed (like after antibiotics), diarrhea can occur.

• Probiotics help by restoring a healthy balance of gut bacteria.

• They have shown benefit in:

  • acute diarrhea

  • antibiotic-associated diarrhea

  • infectious diarrhea

Two probiotic strains shown to be effective are ______ and ______.

Lactobacillus GG, Saccharomyces boulardii

Loperamide - MOA

• Stimulates μ (mu) and δ (delta) opioid receptors in the gut.

• 40–50 times more potent as an antidiarrheal than morphine.

• Slows gut motility → increases transit time.

• Has antisecretory effects against toxins (cholera, some E. coli).

• Increases anal sphincter tone.

• Overall, more effective than diphenoxylate or difenoxin.

Loperamide - Pharmacokinetics

• Very poor penetration into the CNS → low abuse potential.

• Half-life (t½) ≈ 11 hours.

Loperamide powerfully reduces diarrhea by slowing gut movement and blocking secretions, but stays out of the brain (safe from abuse).

Diphenoxylate & Difenoxin - MOA

• Stimulate μ (mu) and δ (delta) opioid receptors in the GI tract.

• More potent antidiarrheals than morphine.

• Often combined with atropine (anticholinergic) → reduces motility further, and adds side effects to discourage abuse.

Diphenoxylate & Difenoxin - Pharmacokinetics

• Diphenoxylate is rapidly converted (de-esterified) into its active metabolite difenoxin.

• Both are extensively absorbed orally.

• Half-life (t½) ≈ 12 hours.

• At high doses (40–60 mg/day), they cross the blood-brain barrier (BBB) → risk of CNS effects/abuse.

Diphenoxylate & Difenoxin - Adverse Effects

with excessive use/overdose

• CNS depression (sedation).

• Constipation.

• Toxic megacolon (serious inflammatory complication).

• Anticholinergic effects from atropine → dry mouth, blurred vision, etc.

Diphenoxylate → metabolized to difenoxin, both strong antidiarrheals, but risk of CNS effects + abuse at high doses (that’s why atropine is added).

Tincture of Opium & Codeine

Tinctures of Opium

• Paregoric (Camphorated Tincture of Opium) = ~0.4 mg/mL morphine.

• Laudanum (Deodorized Tincture of Opium) = 10 mg/mL morphine (much stronger).

• Both can stop diarrhea because they’re opioids, but:

  • Not preferred due to high abuse potential.

  • Risk of severe overdose, especially if confused between Paregoric and Laudanum.

Tinctures of opium are effective antidiarrheals, but risky (abuse + overdose).

Tincture of Opium & Codeine

Codeine

• Codeine = the 2nd most common alkaloid in opium.

• Can treat diarrhea, but it crosses the BBB, so risk of CNS effects.

• An opioid that stays out of the brain would be safer for diarrhea treatment.

Codeine works but isn’t ideal because it enters the brain.

Eluxadoline

• indicated for IBS-D (irritable bowel syndrome with diarrhea)

• ↓ stool frequency, ↓ urgency, and ↓ abdominal pain.

Eluxadoline - MOA

• Acts on gut opioid receptors:

  • μ-opioid receptor agonist

  • κ-opioid receptor agonist

  • δ-opioid receptor antagonist

• High affinity for μ, low affinity for δ.

• Effects:

  • Slows colonic transit (slower bowel movement).

  • Increases fluid absorption.

  • Reduces visceral hypersensitivity (less pain) without fully blocking gut motility.

Eluxadoline helps IBS-D by binding gut opioid receptors → slows transit, absorbs fluid, reduces pain, but still allows some motility.

Eluxadoline - PK + Adverse Effects

PK

• Very low oral absorption: < 10% bioavailability

• Half-life (t½) ≈ 5 hours.

Adverse Effects

• Generally well tolerated.

• Little to no abuse potential (because poor absorption + gut-specific action).

• Common (<10%): constipation and nausea.

• Serious risk: pancreatitis, especially in patients without a gallbladder (cholecystectomy).

Eluxadoline stays mostly in the gut (low absorption), safe from abuse, but can cause constipation, nausea, and pancreatitis in patients missing a gallbladder.

Octreotide - MOA

• Octreotide = synthetic analog of somatostatin.

• Mimics somatostatin’s effects:

  • ↓ gastric acid secretion

  • ↓ GI hormones (gastrin, CCK, VIP, motilin, secretin)

  • ↓ water and electrolyte secretion

  • ↓ GI motility

Octreotide - Pharmacokinetics

• Not absorbed orally → given subcutaneous (sub-Q), 2–3 times daily.

• Half-life (t½) ≈ 90 minutes.

• Long-acting forms (Sandostatin LAR Depot®, Onco LAR®):

  • Biodegradable microspheres.

  • Allow monthly injections in outpatient setting.

Octreotide - Therapeutic Uses

• Refractory diarrhea caused by hormone-secreting tumors.

• Chemotherapy-associated diarrhea.

• HIV/AIDS-associated diarrhea.

Octreotide mimics somatostatin to slow gut activity and secretion; given sub-Q (short-acting) or monthly depot (long-acting); used for severe/refractory diarrhea in cancer, tumors, or HIV/AIDS.

Clonidine - MOA

• Central α₂ adrenergic receptor agonist.

• Lowers BP by reducing sympathetic outflow from the ANS.

• In the GI tract:

  • Affects enteric neurons + enterocytes.

  • ↑ absorption.

  • ↓ secretion.

  • ↑ transit time (slows motility).

Two common adverse effects of clonidine are ______ and ______.

hypotension, fatigue

Clonidine - Therapeutic Uses

• Chronic, refractory diarrhea.

• Opioid withdrawal diarrhea.

• Diabetic diarrhea (due to autonomic neuropathy).

Clonidine slows diarrhea by acting on the nervous system and gut, but can cause low BP and tiredness.

Crofelemer - MOA

• Blocks CFTR (cAMP-stimulated chloride channels) and calcium-activated chloride channels in intestinal cells.

• ↓ chloride secretion → ↓ sodium & water in gut → less fluid loss.

• Result: shorter duration of diarrhea.

Crofelemer comes from the latex of the South American tree ______.

Croton lechleri

Crofelemer is used to treat diarrhea caused by anti-HIV drugs, including ______ and protease inhibitors, and is safe/tolerated.

RTIs