cellular aspects of motility and interaction with some commonly used drugs Flashcards
main role of the GIT and how is this achieved
to maximise absorption of nutrients
achieved by:
1. regulating motility
2. controlling secretion of digestive juices
what and how does the intestinal epithelium sense the lumen contents?
- distention — mechanoreceptors
- osmolality — osmoreceptors
- acidity — chemoreceptors
- digestive products — chemoreceptors
what are causes of receptor activation in the intestinal epithelium?
- hormones
- nerves — short and long reflexes
- paracrine transmission - eg. histamine secretion controlling acid production in the stomach
this is not either a 1 or 2 or 3 response but more 1 and 2 and 3 all together
enteroendocrine cells account for what % of mucosal cells?
1% - they are the main sensory cells
where is gastrin released?
mainly antrum, also duodenum and jejunum
where are CCK and secretin released?
mainly released in upper 1/3 of small intestine, also some in ileum
what is GIP?
used to be gastric inhibitory peptide, now glucose dependent insulinotropic polypeptide
where is GIP released?
duodenum and jejnunum
what is GLP-1?
glucagon-like peptide 1
where is GLP-1?
mainly in ileum and colon, also duodenum and jejunum
describe motilin
important in inter-digestive motility. stimulates migrating motor complex — clears the SI of any debris into the colon — episodic release 2/3 x day
where where is motilin released?
duodenum and jejunum
what is the migrating motor complex used for?
inter-digestive motility
The migrating motor complex (MMC) is a system of electrical waves that “migrate” throughout the small intestine, serving to propel luminal contents all the way from the stomach to the terminal ileum
what are GIP and GLP-1?
incretins which enhance insulin release by endocrine pancreas
describe GI hormones
- all are short chain peptides
- secreted by enteroendocrine cells found in the mucosa into the blood
- target various regions of GI and glands
- many have effects on nervous system
all neurons involved in the short reflex are part of what?
enteric nervous system = 100 million neurons in the myenteric and submucosal plexus
what excitatory substances are there in the ENS?
ACh, substance P, gastrin release peptide (GRP)
what inhibitory substances are there in the ENS?
nitric oxide and vasoactive intestinal peptide
extrinsic nerves (autonomic nervous system) - parasympathetic effect on GIT
preganglionic fibres synapse with ENS, which can release: ACh, SP, GRP, NO, VIP
— involved in long reflexes eg. vago-vagal (vagus = both afferent and efferent - 80% vagal fibres are sensory)
extrinsic nerves (autonomic nervous system) - sympathetic effect on GIT
postganglionic fibres —> NA = decreased motility and blood flow
no major role in “day to day” motility because we have inhibitory neurotransmitters in the ENS
what are the range of neurotransmitters released by enteric nerves?
ACh, SP, GRP, NO, VIP
what are the 2 ways CCK works?
works as a classic hormone and as a paracrine transmitter
describe the signalling complexity of CCK on the gall bladder
classic hormone: CCK released from wall of duodenum and travels in blood to GB, and causes GB contraction
CCK also released as paracrine transmitter, locally stimulating nerves (vagal afferents) — vago-vagal long reflexes — some branches (vagal efferents) stimulate release of ACh on GB to cause GB contraction — some branch of PSNS go elsewhere to sphincter of Oddi. get release of NO and VIP — relaxation of sphincter of Oddi
—> so as GB contracts, the sphincter opens to allow bile to enter the duodenum
what does the GB respond to?
presence of nutrients, peptides and fatty acids in duodenum
what do enterochromaffin cells secrete?
serotonin
what are 90% of enteroendocrine cells?
enterochromaffin cells
other 10% produce hormones such as CCK and secretin
what does released 5-HT stimulate?
afferent neurons in the submucosa via 5-HT receptors
cells contain enzymes which convert _______ to 5-HT
tryptophan
what is 5-HT stored in?
vesicles
what removes 5-HT to terminate signal?
SERT
what is PIEZO2 channel?
mechanosensor involved in 5-HT release
what is PIEZO?
the principle mechanosensing channels in our body
PIEZO1 = touch in skin
PIEZO 2 = other areas of the body
side effect of SSRIs?
diarrhoea
what are SERT mutations linked to and why?
IBS - get inappropriate amounts of 5-HT floating around for longer than it should
where are teh 5-HT reuptake transporters?
epithelial cells around the enteroendocrine cells
what are currently in trials for IBS?
5-HT3 antagonists and 5-HT4 agonists
how does the presence of food lead to food being pushed along?
presence of food = luminal stimulus —> distention —> 5-HT release —> stimulates afferent neurons in ENS —> stimulate efferent neurons which both excite and inhibit smooth muscle contractions —> contraction of food behind and relaxation ahead of food —> food pushed along
where is the vomiting centre?
medulla
how can toxins and cytotoxic drugs (eg in metastatic cancer, ionising radiation) cause vomiting?
cytotoxic drugs and toxins cause release of inappropriate amounts of 5-HT:
can damage the lining of the gut — release of lots of 5-HT from EE cells — stimulates ENS and vagal afferents via 5-HT3R — vagal afferents to vomiting centre in medulla
what are used as useful anti-emetics in chemotherapy?
5-HT3 antagonists
what stimulates vomiting? describe the vomiting process
- retrograde peristalsis from terminal ileum (peristalsis in wrong direction)
- contents of the intestine moved towards the stomach
- distention of upper tract re-enforces urge to vomit
- increase in intra-abdominal pressure (inspiration and contraction of abdominal muslces) — pushes diaphragm up = increased intra-thoracic pressure
- increased IA + IT pressure force stomach contents through oesophagus and U.O.S
- autonomic discharge — nausea, sweating, salivation, increased HR, ventilation
what is the main site for sensing emetic stimuli? what acts on here?
CTZ / area postrema
- toxins such as opiates, digoxin etc, and vestibular nuclei (input from labyrinth), and vagal afferents (convey signals from gut to brainstem)
what acts on the vomiting centre?
vagal afferents (receive input from EC cells), area postrema, higher cortical centres (pain, repulsive sights, and smells and emotional factors)
describe some anti-emetic drugs
- H1 and M1 antagonists
- D2 and 5-HT3 antagonists
- 5-HT3 antagonists, NK1 antagonists (inhibits substance P) and nabilone (CB1 antagonist)
what are opiates?
powerful analgesics for visceral pain in metastatic cancer
what are the side effects of opiates?
- vomiting in 30% of patients (vita CTZ)
- dysphoria (agitation)
- constipation (which needs to be managed as part of palliative care) (main SE affecting virtually everyone)
opioid receptors : mechanism of action
- u,d,k receptors expressed in GIT
- u-receptors of paramount importance in GIT
- receptor activation = G protein (Go) —> direct interactions with channel proteins
- activates K+ channels
- inhibits Ca++ channels
^^ decrease synaptic transmission - stimulates Gi —> decreases cAMP = decreased fluid secretion
what is the main mechanism for analgesia and for decreased GI motility from opioids?
decreased synaptic transmission
what does increased transit time in the colon lead to?
increased water absorbed = harder to move = viscous cycle
opioids reduce ___________ and cause failure of _____________
reduce forward propulsion and cause failure of sphincters to relax
what endogenous opioids are in the GIT?
enkephalins and endomorphins
how do endogenous opioids affect motility?
decrease motility
what is naloxene affect motility and intestinal secretion?
naloxene = opioid receptor antagonists — increase motility and intestinal secretion
opioids as anti-diarrhoeal drugs?
mu-receptor agonists
- loperamide = immodium
- diphenoxylate + atropine = lomotil
= peristalsis, decreases gastric emptying
