case 4 - cellular aspects of motility and interaction with commonly used drugs Flashcards
what are the principles of control
maximise absorption of nutrients
Achieved by:
regulating motility
Controlling secretion of digestive juices
(Very little control of absorption)
= excellent ‘scavenger,’ evolved when food was in short supply
what do mechanoreceptors sense
distension
what do osmoreceptors sense
osmolality
what do chemoreceptors sense
acidity and digestive productd
what does receptor activation cause
Hormones
Nerves: a) short reflexes and b) long reflexes
Paracrine transmission
You can’t compartmentalise these responses, these responses all happen together
what are the main sensory cell
enteroendocrine cells
what do microvilli do
sense lumen contents or movement
where do you have stored hormone transmitter
on the blood side of the lumen
what are incretins and what are exampls
GIP and GLP-1 are incretins which enhance insulin release by endocrine pancreas
what is motililin
important in inter-digestive motility
what are all GI hormones
all short chain peptides
Secreted by enteroendocrine cells found in the mucosa into the blood
Target various regions of the GI and glands
Many have effects on nervous system
what is CCK
secreted by the intestine
Affects the pancreas, gall bladder, stomach
Affects CNS - satiety
what is the enteric nervous system
100 million neurones in the myenteric and submucosal plexus
what are the excitatory substances in the ENS
substance P, gastrin releasing peptide and ACH
what are the inhibitory substances in the ENS
nitric oxide, vasoactive intestinal peptide
what is the short reflex
all neurones involved are part of the ENS
what are the extrinisic nerves
the autonomic nervous systems
features of the parasympathetic
preganglionic fibres synapse with ENS (which can release: ACH, SP, GRP, NO, VIP)
involved in long reflexes e.g vago-vagal (vagus = both afferent and efferent - 80% vagal fibres are sensory)
features of the sympathetic
post-ganglion fibres —> noradrenaline = decreased motility and decreased blood flow
- No major role in ‘day to day’ motility
what does CCK do
CCK causes contraction of the gall bladder
It also stimulates nerves and travels up to the dorsal vagal complex which can stimulate release of ACh - also cause contraction of the gall bladder
what happens at the Sphincter of Oddi
relaxes - NO/VIP
what is the main mechanoreceptor and chemoreceptor sensory cell of the GI tract
enterochromaffin cells - serotonin
what happens if these cells are stimulated
they release serotonin - 5HT
what does SERT do
removes 5HT to terminate signal
SERT mutations also linked to IBS
what is the PIEZO 2 channel
a mechanoreceptor
what leads to contraction
Ach and SP lead to contraction - excitatory motor neurone
what leads to relaxation
VIP and NO lead to relaxation - inhibitory motor neurone
what is a luminal stimulus
5HT - intrinsic primary afferent neurone
what is a useful anti emetic used in chemo
5HT3 antagonists
how does vomiting happen
toxins and cytotoxic drugs stimulate 5HT which stimulates 5HT3R which goes up the vagal afferent and goes to the vomiting centre in the medulla
what is vomiting
retrograde peristalsis from terminal ileum
Contents of the intestine moved towards the stomach
Distension of upper tract re-enforces urge to vomit
what happens if there is increased intra abdominal pressure
pushes the diaphragm which leads to increased intrathoracic pressure
what does this cause
increased pressure forces stomach contents through the oesophagus and UOS
what anti emetic is used for motion
H1 antagonist
what anti emetic is used for motion sickness
M1 antagonist
what are examples of cytotoxic drugs
5HT3 antagonist
NK1 antagonist
Naboline (CB1)
what are the side effects of opioids
vomiting in 30% of patients
Dysphoria (agitation)
Constipation which needs to be managed as part of palliative care
what is the mechanism of action of opioid receptors
mu, delta and kappa receptors expressed in GI tract
mu-receptors of paramount importance in GI
Receptor activation = G protein (G0) —> direct interactions with channel proteins
Activates K+ channels = decreased synaptic transmission
Inhibits Ca2+ channels = decreased synaptic transmission
Stimulates Gi (Decreased cAMP) = decreased fluid secretion
what is the main mechanism for analgesia and for decreased GI motility and what does this lead to
Decreased synaptic transmission = main mechanism for analgesia and for decreased GI motility which leads to increased transit time in colon which leads to increased H20 absorbed. This leads to constipation.
what is inhibited by opioids and what does this lead to
the inhibitory motor neurone is inhibited by opioids - leads to no relaxation of sphincters (VIP/NO)
Opioids reduce forward propulsion and cause failure of sphincters to relax
what are endogenous opioids
Enkephalins and endomorphins in GI tract
Endogenous opioids leads to decreased motility
Naloxone (opioid receptor antagonist leads to increased motility and increased intestinal secretion
what opioids are used as anti-diarrhoea drugs
mu receptor agonists
Loperamide - Immodium
Diphenoxylate + atropine - Lomotil = peristalsis and decreased gastric emptying
what is the conclusion of this
nutrient sensing is an important and emerging field
Serotonin has a pivotal role controlling GI function
Opiates are still essential for analgesia, but have problematic side effects
