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Pathophysiology of Diarrhea
Two major mechanisms for diarrhea?
Decreased absorption & Increased secretion
Most common cause of osmotic diarrhea?
Major cause of secretory diarrhea?
Increased secretion of electrolytes (cholera, WDHA syndrome) & fluid (celiac sprue; overabundance of crypt cells)
What stimuli are associated with secretory diarrhea?
Mucosal/submucosal, Blood hormone, Luminal
What cellular signals are mediated by enterotoxins?
cAMP, cGMP, Ca++
How does cholera work?
A subunit enters cell & turns on adenylate cyclase to max levels
Turns off NaCl pump
Crypt enterocyte mechanism of CT?
cAMP -> CFTR -> Cl secretion
Endocrine cell mechanism of CT?
5HT & PGE2 release -> Activate neural arc
(myenteric plexus) -> Neurons release
VIP and Ach -> Crypt enterocyte Cl secretion
What are some targets of CT?
Cl ion channel (cAMP has a +ive effect) & NaCl transporter (cAMP has a -ive effect)
What is a common feature among bacterial toxins in secretory diarrhea?
Stimulate Cl- secretion
No morphological damage
No impairment of Na-dependant solute transport
What is another way of causing secretory diarrhea?
Hormone producing tumors (hormones bind to enterocytes)
Causes of inflammatory diarrhea?
Intestinal infections, C. difficle colitis, Inflammatory bowel disease (ulcerative colitis, Crohn's disease), Other Colitides (radiation, ischemia)
How is indirect & direct secretion stimulated?
By inflammatory mediators such as myofibroblasts, macrophages, neutrophils, eosinophils, mast cells
What are some mechanisms of inflammatory diarrhea?
1. Stimulated secretion & inhibited absorption
2. Stimulation of enteric nerves causing propulsive contractions & stimulated secretions
3. Mucosal destruction & increased permeability
4. Nutrient maldigestion & malabsorption
What are some treatments of acute diarrhea?
Fluid and electrolyte replacement, Pharmacologic agents, Antimicrobial agents
What are some ways to stimulate electrolyte & water absorption?
Glucose/amino acids (reduce net secretion)
Opiates and derivatives (helps slow peristalsis)
What are the ways that anti-diarrheal medication works?
1. Increased Intestinal Absorption (Stimulate absorptive processes, Increase absorption through delayed transit)
2. Decreased Secretion (Inhibit active anion secretion and secondary water movement)
What are some anti-diarrheal agents?
• Adsorbents, anti-cholinergics (slow down CNS overview of peristalsis)
• Opiates and derivatives
• Anti-secretory agents
What are some future anti-diarrheal drugs?
- "Super" ORS solutions
- Oral immunoglobulins
- Receptor antagonists
- CFTR inhibitors
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