What is the predominant ANS tone in the GI?
What is the effect of sympathetic input into the GI on the walls? What receptors mediate this?
the walls of the GI relax via a2 and B2 binding
What is the effect of sympathetic input into the GI on the sphincters? What receptors mediate this?
they contract via a1 binding
What is the effect of sympathetic input into the GI on secretions?
There is none
What is the effect of parasympathetic input into the GI on the walls? What receptors mediate this?
contraction via M3 receptors (parasympathetics also cause sphincters to relax via M3 binding and secretions to increase via M3 binding)
What are the effects of cholinergic (Ach) agonists (or AchE inhibitors)?
Bronchorrhea, Bronchospams, Bradycardia
What are the effects of cholinergic (Ach) antagonists (or AchEs)?
constipation and urinary retention
large bronchiole dilation
decreased glandular secretions
restlessness, confusion, delirium, hallucinations
What is the enteric nervous system?
The ENS is involved in sensorimotor control of the GI and this consists of both afferent sensory neurons and a number of motor nerves and interneurons that are organized principally into two nerve plexuses: the myenteric (Auerbach's) plexus and the submucosal (Meissner's) plexus.
Where is the myenteric plexus located and what does it do?
It's located bettwen the longitudinal and circular muscle layers of the GI wall and plays an important role in the contraction and relaxation of GI smooth muscle
What does Meissner's plexus do?
It's involved in secretory and absorptive functions of the GI epithelium, local blood flow, and neuroimmune activities
What is the primary neurotransmitter of the ENS?
What other neurotransmitters are involved in ENS control/modulation?
Dopamine (pre- and postsynaptically inhibit Ach release and relax the esophageal sphincter)
Enkephalin and related opiod peptides
Serotonin (5-HT) (promote Ach release)
ATP, CGRP, CCK
What is Metoclopramide?
A drug used to treat N/V and gastroparesis via its gastrokinetic actions
How does Metoclopramide work?
This drug possesses both dopaminergic (inhibits pre and postsynatic D2 receptors to promote Ach release and prevent relaxation of the esophageal sphincter and stomach) and serotonergic modulatory activity (stimulatory to promote Ach release), leading to coordinated contractions that enhance motility in the upper GI tract
What is the major downside of Metoclopramide?
it causes tardive dyskinesia (involuntary movements of the tongue, lips, face, trunk, and extremities) and
akathisia (movement disorder characterized by a feeling of inner restlessnes and a compelling need to be in constant motion)
-cardiac arrhythmias and bradycardia
What part of Metoclopramide causes BOTH tardive dyskinesia and akathisia?
the dopamine modulation
What are the main types of laxatives?
dietary fiber and bulk-forming
How do antidiarrheals work?
they work to decrease stool fluidity (i.e. water absorbers), to antagonize cholinergic NS activity, or to activate the opiate receptors in the ENS
What is Inflammatory Bowel Disease?
this is a term that encompasses ulcerative colitis and Crohn's disease
What causes IBD?
There is suggested dysbiosis of normal intestinal homeostatic relationship between intestinal mucosa and normal commensals, leading to inflammation (including TNFa)
What are some TNFa-antagonists used in the tx of IBD?
What are natalizumab and vedolizumab?
these bind the a4B7 integrin on T cells in the bloodstream, blocking its interaction with MAdCAM-1, which is mainly expressed on gut endothelial cells, to prevent extravasation of T cells into tissue (mostly used for UC)
What are the AEs of a4B7 integrin inhibitors (natalizumab and vedolizumab)?
-immunosuppression (avoid giving live vaccines during tx)
-progressive multfocal leukoencephalopathy
What causes the rare progressive multfocal leukoencephalopathy seen with a4B7 integrin inhibitors?
JC virus, which is normally present and kept under control by the immune system
How would mild UC be treated initially?
Sulfasalazine, and its metabolite 5-ASA, as anti-inflammatories in the gut (note that these work primarily in the gut because they are poorly absorbed)
How should you procede if Sulfasalazine doesnt work for initial UC tx?
systemic glucocorticoids (note that if UC or CD are moderate to severe at presentation, you can start tx with this)
How should you procede if systemic glucocorticoids work but then the UC pt. relapses?
try immunomodulators like thiopurine, and then go to TNF-a inhibitors
How should mild CD be tx initially?
topical glucocorticoids (distal colonic disease) or budesonide (distal ileal involvement)