GIT - Drugs used in constipation & diarrhea

Question 1

Causes of constipation (3)

Answer 1

1. Insufficient intake of food & water
2. Poor bowel motility & contractibility
3. Obstruction (high/low, intrinsic lesions/extrinsic conditions)

Question 2

Classes of laxatives & examples

Answer 2

Physical

1. Bulk-forming Laxatives (Psyllium, Methylcellulose, Polycarbophil)
2. Stool Surfactant Agents (Softeners) (Docusate, Glycerin, Mineral Oil)
3. Osmotic Laxatives (Sorbitol, lactulose, magnesium hydroxide, balanced polyethylene glycol - PEG)

Physiological

4. Stimulant Laxatives (Cathartics) (Aloe, Senna, Cascara, Bisacodyl)
5. Chloride Channel Activators (Lubiprostone)
6. Opioid Receptor Antagonists (Methylnaltrexone bromide, Alvimopan)
7. Serotonin 5-HT4 Receptor Agonists (Tegaserod, Cisapride, Prucalopride)

Question 3

Mechanism of action of bulk-forming laxatives

Answer 3

Indigestible, hydrophilic colloids (fiber) - absorb water, form bulk, emollient gel that distends colon (increased stool mass) - promotes peristalsis

Question 4

Toxicity of bulk-forming laxatives (2)

Answer 4

1. Bacterial digestion of plant fibers in the colon - flatus, bloating, abdominal pain
2. Interacts with absorption of other drugs

Question 5

Mechanism of action of stool surfactant agents

Answer 5

1. Lowers surface tension - allows water & lipids to penetrate
2. Mineral oil: lubricates bowel + retards water absorption from stool

Question 6

Toxicity of mineral oil (3)

Answer 6

1. Not palatable (mix with fruit juice)
2. Aspiration - severe lipid pneumonia
3. Long term use - impair absorption of fat soluble vitamins A, D, E, K

Question 7

Mechanism of action of osmotic laxatives

Answer 7

Osmotically-mediated water movement into bowel increases stool liquidity & volume - stimulates peristalsis

Question 8

Toxicity of osmotic laxatives + Contraindications (3+1)

Answer 8

1. Colonic bacteria act on sugars to produce gas - severe flatus & abdominal cramps
2. Maintain adequate hydration by increasing oral fluid intake (more water moving into bowel)
3. Sodium phosphate - hyperphosphatemia, hypernatremia, hypocalcemia, hypokalemia, cardiac arrhythmias, acute renal failure (due to tubular deposition of calcium phosphate)
4. Frail, elderly patients/on diuretics, unable to maintain adequate hydration, have renal insufficiency/cardiac disease

Question 9

Mechanism of action of stimulant laxatives

Answer 9

Produce migrating colonic contractions, poorly understood - may include direct stimulation of enteric nervous system or colonic electrolyte & fluid secretion

Question 10

Uses of stimulant laxatives

Answer 10

1. Bisacodyl + PEG for colonic cleansing prior to colonoscopy

Question 11

Toxicity of stimulant laxatives (3)

Answer 11

1. Long term/chronic use by neurologically impaired/bed bound - dependence, destruction of myenteric plexus - colonic atony & dilation
2. Aloe, Senna, Cascara - brown pigmentation of colon (melanosis coli) with chronic use & possible carcinogenesis
3. Phenolphthalein withdrawn - cardiac toxicity

Question 12

Mechanism of action of chloride channel activators

Answer 12

Stimulate type 2 chloride channels (CIC-2) in small intestine - increases chloride-rich fluid secretions (water follows) & stimulates motility & shortens intestinal transit time

Question 13

Toxicity of chloride channel activators + Contraindications (2+1)

Answer 13

1. Return of constipation after discontinuation
2. Nausea due to delayed gastric emptying (30% of patients)
3. Pregnancy - thought to cross placental barrier, possibly teratogenic

Question 14

Mechanism of action of methylnaltrexone bromide & alvimopan

Answer 14

Blocks intestinal mu-opioid receptors

Question 15

Uses of methylnaltrexone bromide

Answer 15

Opioid-induced constipation in patients receiving palliative care administered SQ every 2 days

Question 16

Uses of alvimopan

Answer 16

Post operative ileus in hospitalised patients after GI surgery, orally ≤5h before surgery & twice daily after surgery

• does not readily cross BBB - does not block CNS analgesic effects

Question 17

Toxicity of alvimopan

Answer 17

Cardiovascular toxicity - restricted to short term use in hospitalized patients

Question 18

Mechanism of action of serotonin 5-HT4 receptor agonists

Answer 18

Stimulates presynaptic 5-HT4 receptors on submucosal intrinsic primary afferent neurone (IPAN) terminals - enhance release of neurotransmitters eg CGRP - stimulates enteric neurons to promote peristaltic reflex & colonic mass movement

Question 19

Toxicity of serotonin 5-HT4 receptor agonists

Answer 19

1. Tegaserod, Cisapride - 5-HT4 partial agonists - adverse cardiovascular effects

Question 20

Classes of anti-diarrheals & examples

Answer 20

1. Opioid Agonists (Loperamide, Diphenoxylate)
2. Colloidal Bismuth Compounds (Bismuth subsalicylate, bismuth subcitrate potassium)
3. Kaolin & Pectin
4. Bile Salt-Binding Resins (Cholestyramine, Colestipol, Colesevelam)
5. Somatostatin-like Peptides (Octreotide)
6. Lyophilizate of Lactobacillus acidophilus (Lacteol forte)

Question 21

Mechanism of action of opioid agonists

Answer 21

Acts on enteric nervous system - increases colonic transit time

Question 22

Toxicity of opioid agonists

Answer 22

1. Potential for CNS effects including addiction & abuse
   - Loperamide: does not cross BBB
   - Diphenoxylate: high dose - CNS effects, long term - dependence
   - Preparation often includes atropine to discourage overdose (anticholinergic adverse effects eg dry mouth + antidiarrheal action)

Question 23

Mechanism of action of colloidal bismuth compounds

Answer 23

Precise mechanisms unknown

1. Rapid dissociation of bismuth subsalicylate in stomach - absorption of salicylate
2. Salicylate inhibits intestinal PG production & Cl secretion
3. Reduces stool frequency & liquidity in acute infectious diarrhea

Question 24

Uses of colloidal bismuth compounds (2)

Answer 24

1. Antimicrobial effects binds enterotoxins - Traveller’s Diarrhea
2. Mucosal Protective agent in acid-peptic diseases

Question 25

Toxicity of colloidal bismuth compounds (3)

Answer 25

1. Harmless blackening of stool & darkening of tongue (liquid formulations) 2. Bismuth toxicity (prolonged use, rare) - encephalopathy (ataxia, headaches, confusion, seizures) 3. Salicylate toxicity (high dose)

Question 26

Mechanism of action of kaolin & pectin

Answer 26

Absorbs bacterial toxins & fluids - decreased stool liquidity & number

Question 27

Uses of kaolin & pectin

Answer 27

1. Acute diarrhea, seldom used chronically

Question 28

Toxicity of kaolin & pectin (2)

Answer 28

Not absorbed, little risk 1. Constipation 2. Binds & inhibits absorption of other medications

Question 29

Mechanism of bile salt-binding resins (antidiarrheal)

Answer 29

1. Conjugated bile salts are normally absorbed in the terminal ileum 2. Diseases of the ileum (eg CD)/Surgical resection - malabsorption of bile salts - colonic secretory diarrhea 3. Binds to bile salts - alleviates diarrhea caused by excess fecal bile salts

Question 30

Toxicity of bile salt-binding resins (antidiarrheal) (3)

Answer 30

1. Bloating, flatulence, constipation, fecal impaction 2. Exacerbation of malabsorption of fat if underlying deficiency is present 3. Binds to some drugs

Question 31

Mechanism of action of octreotide

Answer 31

Similar to somatostatin - inhibits release of transmitters & hormones eg gastrin, VIP, 5-HT - reduces intestinal & pancreatic secretions - slows GI motility & inhibits gall bladder contraction

Question 32

Uses of octreotide (2)

Answer 32

1. Secretory diarrhea caused by GI neuroendocrine tumours (carcinoid, VIPoma) 2. Diarrhea due to vagotomy, gastric dumping syndrome, short bowel syndrome, AIDS

Question 33

Toxicity of octreotide (5)

Answer 33

1. Steatorrhea - fat soluble vitamin deficiency - due to impaired pancreatic secretion 2. Nausea, abdominal pain, flatulence, diarrhea 3. Formation of gall sludge/stones 4. Hypothyroidism (long term) 5. Bradycardia

Question 34

Mechanism of action of lacteol forte

Answer 34

Adheres onto the surface of intestinal cells - normalizes intestinal flora by competitive exclusion/prevents overcolonization of these organisms

Question 35

Uses of lacteol forte

Answer 35

1. Bacterial/Traveler's Diarrhea

Question 36

Toxicity of lacteol forte + Contraindications

Answer 36

Not systemically absorbed, little risk - Important to maintain hydration 1. Lactose intolerance - formulation contains lactose monohydrate