Therapeutics GI Sandoval Flashcard

Transepithelial Resistance is high in the ___________ and low in the _____________

Colon (this explains why the colon has reduced absorptive capacity)

Small Intestine

Aldosterone’s role in electrolyte transport in the colon

  • Increases Na+ channel expression, which leads to increased Na+ and H2O absorption by the colon
  • It can also increase K+ efflux, because as Na+ absorption increases, intracellular levels of K+ rise and this leads to increase K+ efflux into the lumen of the colon

Cholera’s Role in Diarrhea

  • The cholera toxin activates adenylyl cyclase, which leads to increased [cAMP]i
  • cAMP opens Cl- channels on the apical surface of intestinal cells
  • As Cl- is effluxed, Na+ follows passively along with water
  • The volume in the intestine exceeds the intestine’s absorptive capacity and diarrhea results

4 Factors of Chronic Diarrhea

  1. Osmotic
  2. Secretory (imbalance in secretion or absorption)
  3. Exudative (structural disruption of of intestinal wall)
  4. Abnormal Intestinal Transit

Opioids

Can be used to treat diarrhea

Act on ;, ;, and ; receptors

;

; receptors

  • Gi-PCR decrease [cAMP]i; which results in decrease intestinal motility
  • Results in increased contact time for fluids to be absorbed
  • Also decreases secretion from intestinal crypt cells

; receptors

  • Involved in increasing intestinal absorption as well as decreasing intestinal secretion

; receptors

  • Involved in decreasing intestinal motility (by decreasing ACh)
  • Also has anti-secretory properties

;

Loperamide

  • An Opioid
  • Peripheral ; receptor agonist
  • Poor CNS penetration
  • Produces constipatory effects without abuse potential
  • 40-50 x more potent than morphine on ; receptors
  • Increases anal sphincter tone
  • Has anti-secretory activity against the cholera toxin and E. coli

Diphenoxylate/Difenoxin

  • An Opioid
  • Active metabolite is Difenoxin
  • Difenoxin is a peripheral ; receptor agonist
  • Anti-diarrheal effects are slightly more potent than morphine but less potent than loperamide
  • Can penetrate the CNS –> administered with sub-therapeutic dose of atropine

Bismuth Subsalicylate

Can be used for diarrhea

  • Anti-Diarrheal
  • Anti-Inflammatory (inhibits COX)
  • Antimicrobial (Bismuth prevents microbes from adhering to intestinal cells and inactivates enterotoxins)
  • Anti-Secretory

Octreotide

Used to treat diarrhea

  • A Somatostatin receptor agonist
  • Somatostatin receptors are Gi-PCR, which have inhibitory actions on the release of many hormones including gastrin, vasoactive intestinal polypeptide, insulin, secretin, and growth hormone
  • Since it is Gi-coupled, it has inhibitory actions on intestinal fluid secretion and motility
  • Octreotide can inhibit severe secretory diarrhea produced by AIDS, diabetes, and hormone-secreting tumors of the pancreas and the GI tract
  • Parenteral only

Causes of Constipation

  • Endocrine disorders
  • Diseases of nervous system
  • Diseases of large intestine
  • Drug-induced

Bulk-Forming Laxatives

  • Indigestible hydrophilic substances that resemble natural dietary fiber
  • Absorb and retain water in the intestinal lumen and thereby increase the mass of intestinal material, causing mechanical distention of the intestinal wall and stimulating peristalsis

Fecal Softeners/Surfactant Laxatives

  • Facilitates the incorporation of water into fatty intestinal material which softens the feces
  • Also alters intestinal permeability to increase net water and electrolyte secretion into the intestine

Stimulant Cathartics

  • Stimulate peristaltic movement of the intestine by local mucosal irritation, promoting evacuation of the colon by altering intestinal fluid and electrolyte absorption
  • May inhibit intestinal Na+/K+ ATPase
  • Increase cAMP –> results in increased secretion of electrolytes and water

Osmotic Laxatives

  • Attract and retain water in the intestinal lumen and increase intra-luminal pressure, thereby stimulating peristalsis
  • Lactulose, sorbitol
  • Polyethylene glycol electrolyte solutions
  • Saline laxatives

Caution with carboxymethylcellulose sodium and psyllium husk

  • Cellulose can reduce intestinal absorption of many drugs (cardiac glycosides, salicylates)
  • Psyllium may bind coumarin derivatives

 

Caution with Lactulose

A disaccharide consisting of galactose and fructose — caution in diabetes

 

Caution with  Saline Laxatives

  • Up to 20% of salt is absorbed
  • May result in electrolyte shifts due to dehydration as they are hypertonic salts

Diphenylmethane Derivatives

  • Bisacodyl
  • Sodium picrosulfate

Active component is BHPM

Anthraquinone Derivatives

  • Senna
  • Cascara

Active component is rhein anthrone

Castor Oil

  • Triglyceride of Ricinoleic acid

Active component is ricinoleic acid

 

Caution with Stimulant Laxatives

  • Prolonged use of stimulant laxatives may result in cathartic colon (controversial)
  • Bisacodyl overdosage
  • Senna may cause abnormal coloring of urine and pseudomelanosis coli (could lead to colon cancer)

Lubiprostone

  • Chloride channel activator (ClC-2) on apical side
  • Does not alter serum electrolyte concentrations
  • Increases intestinal fluid secretion, softens stool
  • Does not produce tolerance
  • Well tolerated
  • No CYP interactions

 

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