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Flashcards in Lower GI Pharmacology Deck (30):

Treatment of most simple constipation

  • proper diet
    • high fiber
  • exercise
  • adequate fluid intake


Classes of laxatives

  • bulk-forming
  • stimulant (irritant)
  • saline (osmotic)
  • wetting agents


Examples of bulk-forming/fiber laxatives

  • psyllium (metamucil)


Mechanism of ation of fiber/bulk-forming laxatives (psylium(Metamucil))

  • ~physiologic mechanism
  • facilitate passage and stimulate peristalsis via absorption of water ==> bulk expansion ==> swells and distends colon


MOA of saline (osmotically active agents) cathartics

  • Nonabsorbable ions in lumen ==> osmotic retention of water in intestine ==> increased peristalsis

  • Can be used in purging doses for food / drug poisoning


Examples of saline (osmotic) cathartics

  • Milk of magnesia [Mg(OH2)]
  • Phosphate enemas
  • Polyethlyene Glycol -- electrolyte solutions (Miralax)
  • Lactulose (Chronulac)


Milk of Magnesia MOA/use

  • Most commonly used cathartics for mild to moderate constipation. 
  • Avoid in renal dysfunction as long term use can lead to electrolyte imbalances.


Polyethlene Glycol -- Electrolyte Solutions (PEGs): Examples & MOA

  • High volume solutions (4 liters of Colyte)
    • bowel cleansing prior to procedures. 
    • sodium and potassium salts prevent net transfer of electrolytes into lumen.
  • Smaller volume solutions (250-500 ml of Miralax)
    • used for difficult to treat constipation
    • Prolonged, frequent, or excessive use may lead to electrolyte depletion.


Typical uses for each class of laxatives

  • laxatives used for tx of acute constipation
  • Fiber/bulk forming = usually first-line
  • saline (osmotic) cathartics = added to fiber as a second step
  • stimulant/irritants = try if fiber/saline fail
  • stool-wetting agents = prevention agents


Administration of fiber/bulk-forming laxatives

  • Effective in 12-24 hrs to 3 days
  • take with 8 oz water/juice


Drawbacks of fiber/bulk-forming laxatives

  • May combine and interact with other drugs (digoxin / salicylates)
  • requires spacing of doses


Examples of stimulat/irritant laxatives

  • Bisacodyl (Dulcolax)
  • castor oil


MOA, onset of Bisacodyl (Dulcolax)

  • = stimulant/irritant laxative
  • ==> increase in peristaltic activity by inducing low-grade inflammation (local irritation) in bowel to promote accumulation of water and electrolytes and stimulation of intestinal motility. 

  • Proposed mechanisms include activation of prostaglandin-cAMP and NO-cGMP pathways.

  • Usually active within 6-10 hrs orally or 15-60 min rectally

  • Safe for chronic use in recommended doses


Drawbacks of bisacodyl

  • Effective, but potentially dangerous side effects (electrolyte / fluid deficiencies, severe cramping).   
  • BUT most widely abused class
  • wide variation in the effective dose in individual patients ==> same dose may result in a lack of effect in some, but may produce cramping and fluid loss side effects in others


Examples of wetting agents and emollients

  • sufractant (docusate [Colace])
  • lubricant (mineral oil, olive oli)


Surfactant: examples, MOA

  • ex: docusate [Colace]
  • Acts as stool-softener (facilitates admixture of aqueous and fatty substances)
  • Role is primarily prevention. 
  • Used in patients with cardiovascular disease / hernia / postpartum patients. 
  • Often used in combination with stimulant laxative when initiating opioid analgesic therapy.


Lubricant: Examples, MOA, drawbacks

  • e.g.: mineral oil, olive oil
  • coats fecal contents preventing colonic absorption of fecal water. 
  • Use with caution in very young / elderly due to potential for aspiration into lungs.


General approach to diarrhea tx

  • most patients w/sudden onset of diarrhea have benign, self-limiting illness that requires no tx/evaluation
  • severe cases w/infants, children, elderly: tx = oral rehydration therapy
  • most agents provide symptomatic relief of mild causes of acute diarrhea, but do not address underlying cause


Opioids: Examples & MOA

  • e.g.: loperamide (Imodium)
  • MOA: mediated via opioid receptors, including effects on intestinal motility (m), intestinal secretion (d), and absorption (m and d). 
  • Loperamide also has anti-secretory activity against cholera toxin


Opioids: typical use

  • Loperamide is effective against traveler’s diarrhea
    • alone or in combination w/antimicrobial agents
  • Use should be discontinued if no improvement in 48 hours.


Opioids: side effects

  • Low addiction liability for acute use due to low water solubility (difficult to dissolve and then inject)
  • Few adverse effects but overdosage can cause CNS depression (esp. in children) and paralytic ileus
  • May worsen Shigella infections


Polycarbophil (Mitrolarr): MOA, use

  • Recognized by FDA as safe and effective (marked capacity to bind free fecal water).
  • Useful in diarrhea (absorbs 60X weight in H2O) and constipation (prevents fecal desiccation).


Examples of adsorbents

  • kaolin/pectin (Kapectolin)
  • Bismuth subsalicylate (PeptoBismol)


Adsorbents: MOA, use

  • adsorb “toxins” that cause irritation (of doubtful value); can also adsorb drugs, nutrients, digestive enzymes.
  • Generally, take after each loose bowel movement until diarrhea controlled. 
  • Can usually manage mild to moderate diarrhea (promote “formed stools” and perception of decreased fluidity, but small effect on fluid volume excreted).


Adsorbents: drawbacks

  • little effects on actual fluid volume excreted
  • avoid use of bismuth subsalicylate in children under 12
    • risk for Reye's syndrome


General pharm tx for IBS

  • low dose tricyclic antidepressants
    • goal: relieving abdominal pain and discomfort
  • antidiarrheal agents [loperamide] if diarrhea
    • goal: improving bowel function
  • fiber supplements / osmotic laxatives if constipation
    • goal: improving bowel function
  • Serotonin 5-HT3 Antagonists (Alosetron [Lotronex])
  • Serotonin 5-HT4 Agonists (Tegaserod [Zelnorm])


Alostetron [Lotronex]: MOA & use

  • MOA: Block of 5-HT3 receptors on sensory and motor neurons reduces pain and inhibits colonic motility.

  • Use: Currently restricted to use only for treatment of severe IBS in women with diarrhea as the prominent symptom that have not responded to conventional therapies. 


Alosetron [Lotronex]: Side effects

  • Constipation in 30% of patients, requiring discontinuation in 10%. 
  • Ischemic colitis in 3 of 1000 patients with some fatalities has led to restricted use


Tegaserod[Zelnorm]: MOA, use

  • MOA: Agonist at serotonin 5-HT4 receptors that leads to stimulation of release of neurotransmitters involved in peristaltic reflex, promoting gastric emptying and intestinal motility
  • Use: Use is now restricted (as is alosetron) to women under 55, approved for treatment of IBS patients with predominant constipation or chronic idiopathic constipation who haven’t responded to other treatments.


Tegaserod [Zelnorm]: Side effects

  • Some diarrhea (10%) early in therapy that resolves within first few days of treatment. 
  • Linked with heart attacks, strokes, and unstable angina leading to restricted use.