Lower GI pharmacology

Question 1

How can Constipation happen?

Answer 1

• Decreased GI motility

* Or excess fluid removal and thus fecal thickening or congealing

Question 2

Inspissated = ?

Answer 2

Inspissated = thickened or congealed

Question 3

How might diarrhea happen?

Answer 3

• Increased GI motility
• Or increased osmotic load in intestine
• Or increased secretion of water and electrolytes into intestine and now colon can’t reabsorb it all
○ Or a combo of these processes
• This allows us to categorize into different groups

Question 4

What OTHER drugs have constipation as a side effect?

• These can be used, in theory, as drugs for diarrhea OR you might need to combine laxative therapy with these drugs

Answer 4

• Calcium channel blockers
○ Verapamil
• Opioid analgesics
• Antimuscarinics
○ Or drugs with antimuscarinic side effects
○ TCAs, antipsychotics, 1st generation antihistamines, parkinsonian agents
• Aluminum and calcium containing antacids plus calcium supplemnts
○ Especially calcium carbonate
• Chemotherapeutic vinca alkaloids

Question 5

How is constipation treated chronically?

Answer 5

• Lifestyle
○ Higher fiber
○ Higher movement, especially abdominal muscles
○ Adequate fluid intake
• Laxatives are really only used for acute management

Question 6

What are the bulk-forming laxatives?

Answer 6

• Psyllium
• Methylcellulose
○ Leads to swelling of stool and distension of colon

Question 7

What are the saline/osmotic laxatives?

Answer 7

• Magnesium hydroxide
• Lactulose
○ Increases fluid volume in colon

Question 8

What are the wetting agent laxatives?

Answer 8

• Docusate
• Mineral oil
○ These moisten the stool to ease passage

Question 9

What are the stimulant/irritant laxatives?

Answer 9

• Bisacodyl
• Senna
○ Stimulate enteric nerves to increase GI motility

Question 10

Why are fiber/bulk-forming laxatives supposed to be tried first?

Answer 10

• They most closely approximate the natural way of stimulating defecation
○ Facilitate passage and stimulate perisalsis via absorption of water and subsequent bulk expansion
• Effective in 12-24 hours to 3 days
○ Take with 8oz water or juice
• Safe to combine with other drugs
• Psyllium and methylcellulose

Question 11

What are the osmotically active laxatives and when are they used?

Answer 11

• Milk of magnesia or magnesium citrate
○ Mild to moderate constipation
○ Avoid in renal dysfunction
• Phosphate enemas
○ Reserve this for fecal compaction
• Polyethylene glycol (PEG) (with electrolyte solution)
○ High volume solutions
§ 4L of golytely or colyte
§ Bowel cleansing prior to radiologic, surgical or endoscopic procedures
§ Sodium and potassium salts to prevent net transfer of electrolytes into lumen
○ Smaller volume solutions
§ 250-500mL of miralax
§ Refractory constipation
§ Daily dose for 2 weeks or less duration
§ Prolonged use can lead to electrolyte depletion (also watch for bulemia and abuse)
• Lactulose
○ Dissacharide metabolized by colonic bacteria to low molecular weight acids leading to osmotic diarrhea and increased colonic peristalsis
○ Useful in elderly, used in acute situations

Question 12

Which osmotically active agents should you avoid in renal failure?

Answer 12

• Mg salts, can lead to hypermagnesemia

Question 13

What is the most widely abused class of laxatives?

Answer 13

• Bisacodyl (stimulant or irritant)

* Has electrolyte and fluid deficiencies as most severe side effect or consequence

Question 14

What laxative agent would you use in a patient with cardiovascular disease, hernia, or postpartum patients?

Answer 14

• Something PREVENTATIVE
	• A stool softener
		○ Stool-wetting and emollient agents
	• Surfactant (docusate)
	• Lubricant (mineral oil/olive oil)
		○ Helps things move along

Question 15

Methylnaltrexone and naloxegol are examples of what type of drug? When might you use these?

Answer 15

• Peripherally acting opioid antagonists
  
  • In patients on chronic opioids for non-cancer pain that need laxatives
  • These are designed to NOT mess with the opioid analgesia at all, but just keep the opioids from lowering GI motility

Question 16

What OTHER drugs have diarrhea as their side effects?

Answer 16

• SSRIs
  
  • Colchicine
  • NSAIDs
  • Digoxin
  • Misoprostol
  • Antibiotics (especially broad spectrum)
  • Muscarinic agonists

Question 17

While most diarrhea is self-limiting, when and in whom are you worried about severe complications?

Answer 17

• Infants, children, elderly.
  
  • Concern here is fluid loss, electrolyte imbalances and hypotension
  • Oral rehydration therapy is the mainstay here. Remember that most treatments for diarrhea are symptomatic, not targeting the pathophys

Question 18

What are the opioids you can use for antidiarrheal therapy?

Answer 18

• Paregoric
  
  • Opium powder
  • Diphenoxylate + atropine = Lomotil
  • Loperamide = imodium

Question 19

What can go wrong with using opioids to manage diarrhea?

Answer 19

• We are talking about the peripherally acting ones here
  
  • They have low addiction potential b/c of poor BBB crossing
  • They can lead to CNS depression in children
  • Also can lead to paralytic ileus
  • Can worsen shigella infections

Question 20

What opioid receptors are implicated in diarrhea?

Answer 20

• Mu - motility
  
  • Delta - intestinal secretion
  • Mu and delta together - absorption
  • Loperamide has anti-secretory capacity in cholera toxin infection

Question 21

What are the absorbent anti-diarrheals?

Answer 21

• Kaolin
  
  • Pectin
  • Attapulgite
  • Charcoal
  • Bismuth subsalicylate (pepto bismol)

Question 22

What is important to think about with bismuth subsalicylate use?

Answer 22

• Don’t use bismuth subsalicylate in children under 12
○ Salicylate risk for reye’s syndrome
Reye’s (Ryes) syndrome is a rare but serious condition that causes swelling in the liver and brain.

Question 23

What is the rationale behind using adsorbent anti-diarrheals?

Answer 23

• Adsorb toxins that cause irritation (meh)
• Can adsorb drugs, nutrients, digestive enzymes too
• Take after each loose bowel movement until symptoms are controlled
• Use in mild to moderate diarrhea
• Don’t use bismuth subsalicylate in children under 12
○ Salicylate risk for reye’s syndrome

Question 24

Why would somebody with IBS be prescribed TCAs?

Answer 24

• Not for any association with depression or anxiety

* Apparently low dose TCAs help treat symptomatic abdominal pain and discomfort

Question 25

What is alosetron?

Answer 25

• IBS medication - serotonin 5-HT3 antagonist
  
  • Block of 5-HT3 receptor on sensory and motor neurons reduces pain and inhibits colonic motility
  • Extensive P450 metabolism (doesn’t induce, but is metabolized by that system)
  • Main side effect to worry about is ischemic colitis in 3/1000 patients
  • Only use in women with IBS that has diarrhea as the only presenting symptom and is refractory to other treatments. Even then 1/2 patients find relief

Question 26

What is Tegaserod?

Answer 26

• 5-HT4 agonist (pay attention)
  
  • IBS treatment in particular for constipation
  • Leads to release of NT involved in peristaltic reflex promoting gastric emptying and intestinal motility
  • Renal secretion and hepatic metabolism
  • Used in women below 55 with predominant constipation or chronic idiopathic constipation