cellular aspects of motility and interaction with commonly used drugs (lecture series) Flashcards
Regulation of what mechanisms help maximise absorption of nutrients ?
- regulating motility
- controlling secretion of digestive juices in response to the presence of food
Is absorption of nutrients highly controlled or not ?
there is little control of absorption as the mechanisms are always active, rather than turned on in the presence of food
Which organ is considered the “largest sensory organ” in the body ?
intestinal epithelium
What do intestinal mechanoreceptors respond to ?
distention
What do intestinal osmoreceptors respond to ?
osmolality
What do intestinal chemoreceptors respond to ?
- acidity
- digestive products
What does activation of intestinal receptors (mechano, chemo…) result in ?
- hormone release
- reflexes (short and long)
- paracrine transmission
all occurring together
What is paracrine transmission ?
cell to cell communication that alters the activity of neighbouring cells
What are the main sensory cells in the intestine called ?
enteroendocrine cells
What feature of enteroendocrine cells increase their SA ?
Microvilli
What do enteroendocrine cells contain ?
stored hormones and neurotransmitters that can be released into the blood of stimulated
Where is the majority of gastrin released in the GI tract ?
Antrum of the stomach
Where are the 3 places Gastrin is released from?
- Antrum of stomach (main site)
- Duodenum
- Jejunum
Where is the majority of CCK released in the GI tract ?
- Duodenum
- Jejunum
Where are the 3 places CCK is released from?
- duodenum (main site)
- jejunum (main site)
- ileum
Where is the majority of Secretin released in the GI tract ?
- duodenum
- jejunum
Where are the 3 places secretin is released from?
- duodenum (main site)
- jejunum (main site)
- ileum
What are the 2 main places GIP is secreted in the GI tract ?
- duodenum
- jejunum
Where is the majority of GLP-1 released in the GI tract ?
- ileum
- colon
Where are the 4 places GLP-1 is released from?
- duodenum (starts halfway through)
- jejunum
- ileum (main site)
- colon (main site)
What are the 2 main places Motilin is secreted in the GI tract ?
- duodenum
- jejunum
What type of hormone are GIP and GLP-1 ?
Incretins
What is the main role of Incretins ?
enhance insulin release
What is the main role of GIP and GLP-1 ?
enhance insulin release
Are GI hormones long or short chain peptides?
short chain peptides
What type of cell secretes the GI hormones ?
enteroendocrine cells in the mucosa of the epithelium
Between which layers of the GI epithelium does the myenteric plexus lie ?
- longitudinal muscular layer
myenteric plexus - circular smooth muscle layer
Between which layers of the GI epithelium does the submucosal plexus lie ?
- circular smooth muscle layer
submucosal plexus - mucosa
Which 2 plexuses make up the enteric nervous system ?
- myenteric plexus
- submucosal plexus
Are enteric neurones excitatory or inhibitory ?
Both !
What is the main excitatory neurotransmitter released by the enteric NS ?
Acetylcholine
Name the 3 main excitatory neurotransmitters released by the enteric NS …
- acetylcholine
- substance P
- GRP (gastric releasing peptide)
Name the 2 main inhibitory neurotransmitters released by the enteric NS …
- NO (nitric oxide)
- VIP (vasoactive intestinal peptide)
What is a short reflex?
a reflex where all neurones involved are part of the enteric NS
What kind of extrinsic nerve fibres synapse with the enteric NS ?
preganglionic parasympathetic fibres from the autonomic NS
VAGAL NERVE FIBRES
release the same neurotransmitters as the enteric NS
Which type of reflex are parasympathetic nerve fibres involved in, with regards to the GI tract ?
Long reflexes
Are vagal fibres the efferent or afferent leg of GI tract long reflexes ?
both
What % of vagal fibres are sensory ?
80%
What are vago-vagal reflexes an example of ?
long reflexes
What do sympathetic nerve fibres release that has minor impact on gut motility ?
noradrenaline
slight reduction in motility and blood flow
Which neurotransmitter reduces motility and blood flow in the gut ?
noradrenaline via sympathetic fibres
Which GI hormone primarily controls gall bladder function ?
CCK
Cholecystokinin
How does CCK control gall bladder function ?
1. ‘hormonal control’
- presence of nutrients in duodenum causes release of CCK into blood
- CCK travels to gall bladder and causes contraction
2. ‘paracrine transmission’
- presence of nutrients in duodenum causes release of CCK into blood
- CCK stimulates local afferent vagal nerves
- Dorsal vagal complex stimulates vago-vagal (long) reflexes ….
2a. Long reflexes (contraction)
- dorsal vagal complex in brain stimulated
- causes efferent vagal nerves to release Ach onto gall bladder
- causes contraction
2b. Long reflexes (relaxation)
- dorsal vagal complex in brain stimulated
- causes efferent vagal nerves to release NO + VIP onto sphincter of Oddi
- relaxes the sphincter, opening it to allow bile to enter duodenum
What % of enteroendocrine cells are enterochromaffin cells ?
90%
What type of cells are the main mechano/chemo-sensory cells of the GI tract ?
enterochromaffin cells
Which neurotransmitter do enterochromaffin cells secrete ?
serotonin
5-HT
How do enterochromaffin cells show up on a histological stain ?
Small dark brown dots (like moles)
What % of all serotonin in the body is found in the GI tract ?
95% !!
What feature of enterochromaffin cells increases their SA ?
microvilli
What feature of enterochromaffin cells enhances their sensitivity ?
microvilli
What type of neurone does 5-HT stimulate when released from enterochromaffin cells ?
afferent neurones
How do neighbouring epithelial cells stop the action of 5-HT released by enterochromaffin cells ?
The surrounding membrane contains SERT that removes 5-HT from the junction
Why is diarrhoea a side effect of some SSRIs ?
- 5-HT stimulates motility in the gut via afferent neurones
- there are SERT proteins in neighbouring cell membranes that terminate this signal
- if the termination is inhibited then the gut will be continually stimulated
= diarrhoea
What is a potential cause of IBS that is linked to 5-HT ?
SERT mutations, so serotonin action in the GI tract is not terminated sufficiently
How does 5-HT stimulate motility/peristalsis in the gut ?
- food in the lumen stimulates enterochromaffin cells
- 5-HT released
- stimulates afferent neurones in the enteric NS
- these act on efferent neurones
- some have excitatory effects via Ach/SP (behind the food bolus), others are inhibitory via NO/VIP (in front of the bolus)
- causing muscle to both contract and relax in a wave-like pattern = peristalsis
How do toxins and cytotoxic drugs cause vomiting ?
They damage the lining which stimulates enterochromaffin cells to release excessive 5-HT
causes:
- excessive efferent gut motility/churning
- excessive afferent vagal stimulation of vomiting centre in medulla
Which type of 5-HT receptors are found on the afferent vagal neurones that extend to the vomiting centre in the medulla ?
5-HT3 receptors
What is the MOA of antiemetic drugs used in chemotherapy ?
5-HT3 receptor antagonists
= target the receptors found on afferent vagal neurones that extend to the vomiting centre in the medulla
What physiological change normally instigates vomiting ?
retrograde (backwards) peristalsis in the terminal ileum moves contents back towards stomach
What is the physiology of vomiting ?
- retrograde peristalsis
- food moves back towards stomach
- causes distention in upper GI tract …
- stimulates reflexes that urge vomiting
the reflexes:
- increase intra-abdominal pressure which pushes up diaphragm
- causes increased intra-thoracic pressure
- increased pressure forces stomach contents up into oesophagus
- autonomic systems kick in to increase HR, ventilation, salvia, sweating …
What are the 3 main cytotoxic drugs used as antiemetics ?
- 5-HT3 antagonists
- NK1 antagonists
- CB1 agonist
What are the 2 main drugs used as antiemetics for motion sickness ?
- H1 antagonists (antihistamines)
- M1 antagonists
What are the 2 main drugs used as antiemetics for nausea that is not caused by toxins or motion ?
- D2 antagonists
- 5-HT3 antagonists
which drugs are used to treat the pain of metastatic cancer ?
Opiates
What are the main side effects of opiates ?
- constipation (main side effect)
- vomiting (in 30% of patients)
- dysphoria (agitation)
Which pathway do opiates affect that causes nausea ?
The vagal afferent neurones to the CTZ (vomiting centre in the medulla)
Which are the 3 receptor types that opiates act on in the GI tract ?
- μ opioid receptor
- δ opioid receptor
- κ opioid receptor
Which opioid receptor is the most important in controlling GI function ?
μ opioid receptor
How do opiates inhibit synaptic transmission in the gut ?
- μ receptor activated by opiates
- activate G proteins which
- directly interact with channel proteins (activates K channels / inhibits Ca channels)
- causes inhibition of synaptic transmission
MOA for analgesia
How do opiates inhibit fluid secretion in the gut ?
- μ receptor activated by opiates
- activate G proteins which
- stimulates Gi protein to decrease cAMP
- causes decreased fluid secretion
Which effect of opiates is the main mechanism behind their analgesic properties ?
decreased synaptic transmission
- μ receptor activated by opiates
- activates K channels
- inhibits Ca channels
- causes inhibition of synaptic transmission
Which action of opiates is the main mechanism behind their inhibitory effect on GI motility ?
decreased synaptic transmission
- μ receptor activated by opiates
- activates K channels
- inhibits Ca channels
- causes inhibition of synaptic transmission
How do opiates cause constipation ?
- act on μ receptors
- causes inhibition of synaptic transmission = reduced gut motility
- increases transit time in colon
- allows for more water absorption
= harder stool that isn’t as easy to move
How do opioids interfere with gut motility ? (MOA)
- opiates bind to μ receptors in gut
- causing decreased synaptic transmission in the 5-HT peristalsis pathway
- via primarily impacting the inhibitory efferent neurones that normally relax muscle infront of food to propel it forwards
= opioids reduce forward propulsion of food and cause failure of sphincters to relax
What is the impact of opioids on food propulsion through the gut ?
opioids reduce forward propulsion of food and cause failure of sphincters to relax
causing constipation
What are the 2 main families of endogenous opioids ?
- Enkephalins
- Endomorphins
both present in GI tract
What is the function of endogenous opioids in the GI tract ?
reduce gut motility
Due to their side effect of constipation, what could opioids be used as a drug treatment for ?
anti-diarrhoea drugs
What is the target receptor of opioids when used as anti-diarrhoea medications?
μ opioid receptors
What are 2 examples of anti-diarrhoea opioid drugs ?
- Imodium (loperamide)
- Lomotil (diphenoxylate + atropine)
