Lower GI Pharmacology

Question 1

Treatment of most simple constipation

Answer 1

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

Question 2

Classes of laxatives

Answer 2

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

Question 3

Examples of bulk-forming/fiber laxatives

Answer 3

• psyllium (metamucil)

Question 4

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

Answer 4

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

Question 5

MOA of saline (osmotically active agents) cathartics

Answer 5

• Nonabsorbable ions in lumen ==> osmotic retention of water in intestine ==> increased peristalsis
• Can be used in purging doses for food / drug poisoning

Question 6

Examples of saline (osmotic) cathartics

Answer 6

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

Question 7

Milk of Magnesia MOA/use

Answer 7

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

Question 8

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

Answer 8

• 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.

Question 9

Typical uses for each class of laxatives

Answer 9

• 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

Question 10

Administration of fiber/bulk-forming laxatives

Answer 10

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

Question 11

Drawbacks of fiber/bulk-forming laxatives

Answer 11

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

Question 12

Examples of stimulat/irritant laxatives

Answer 12

• Bisacodyl (Dulcolax)
• castor oil

Question 13

MOA, onset of Bisacodyl (Dulcolax)

Answer 13

• = 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

Question 14

Drawbacks of bisacodyl

Answer 14

• 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

Question 15

Examples of wetting agents and emollients

Answer 15

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

Question 16

Surfactant: examples, MOA

Answer 16

• 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.

Question 17

Lubricant: Examples, MOA, drawbacks

Answer 17

• 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.

Question 18

General approach to diarrhea tx

Answer 18

• 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

Question 19

Opioids: Examples & MOA

Answer 19

• 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

Question 20

Opioids: typical use

Answer 20

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

Question 21

Opioids: side effects

Answer 21

• 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

Question 22

Polycarbophil (Mitrolarr): MOA, use

Answer 22

• 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).

Question 23

Examples of adsorbents

Answer 23

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

Question 24

Adsorbents: MOA, use

Answer 24

• 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).

Question 25

Adsorbents: drawbacks

Answer 25

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

Question 26

General pharm tx for IBS

Answer 26

• 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])

Question 27

Alostetron [Lotronex]: MOA & use

Answer 27

• 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.

Question 28

Alosetron [Lotronex]: Side effects

Answer 28

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

Question 29

Tegaserod[Zelnorm]: MOA, use

Answer 29

• 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 I_BS patients with predominant constipation_ or chronic idiopathic constipation who haven’t responded to other treatments.

Question 30

Tegaserod [Zelnorm]: Side effects

Answer 30

• 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.