cellular aspects of motility and interaction with commonly used drugs (lecture series) Flashcards

1
Q

Regulation of what mechanisms help maximise absorption of nutrients ?

A
  1. regulating motility
  2. controlling secretion of digestive juices in response to the presence of food
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2
Q

Is absorption of nutrients highly controlled or not ?

A

there is little control of absorption as the mechanisms are always active, rather than turned on in the presence of food

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3
Q

Which organ is considered the “largest sensory organ” in the body ?

A

intestinal epithelium

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4
Q

What do intestinal mechanoreceptors respond to ?

A

distention

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5
Q

What do intestinal osmoreceptors respond to ?

A

osmolality

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6
Q

What do intestinal chemoreceptors respond to ?

A
  • acidity
  • digestive products
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7
Q

What does activation of intestinal receptors (mechano, chemo…) result in ?

A
  • hormone release
  • reflexes (short and long)
  • paracrine transmission

all occurring together

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8
Q

What is paracrine transmission ?

A

cell to cell communication that alters the activity of neighbouring cells

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9
Q

What are the main sensory cells in the intestine called ?

A

enteroendocrine cells

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10
Q

What feature of enteroendocrine cells increase their SA ?

A

Microvilli

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11
Q

What do enteroendocrine cells contain ?

A

stored hormones and neurotransmitters that can be released into the blood of stimulated

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12
Q

Where is the majority of gastrin released in the GI tract ?

A

Antrum of the stomach

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13
Q

Where are the 3 places Gastrin is released from?

A
  • Antrum of stomach (main site)
  • Duodenum
  • Jejunum
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14
Q

Where is the majority of CCK released in the GI tract ?

A
  • Duodenum
  • Jejunum
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15
Q

Where are the 3 places CCK is released from?

A
  • duodenum (main site)
  • jejunum (main site)
  • ileum
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16
Q

Where is the majority of Secretin released in the GI tract ?

A
  • duodenum
  • jejunum
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17
Q

Where are the 3 places secretin is released from?

A
  • duodenum (main site)
  • jejunum (main site)
  • ileum
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18
Q

What are the 2 main places GIP is secreted in the GI tract ?

A
  • duodenum
  • jejunum
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19
Q

Where is the majority of GLP-1 released in the GI tract ?

A
  • ileum
  • colon
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20
Q

Where are the 4 places GLP-1 is released from?

A
  • duodenum (starts halfway through)
  • jejunum
  • ileum (main site)
  • colon (main site)
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21
Q

What are the 2 main places Motilin is secreted in the GI tract ?

A
  • duodenum
  • jejunum
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22
Q

What type of hormone are GIP and GLP-1 ?

A

Incretins

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23
Q

What is the main role of Incretins ?

A

enhance insulin release

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24
Q

What is the main role of GIP and GLP-1 ?

A

enhance insulin release

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25
Q

Are GI hormones long or short chain peptides?

A

short chain peptides

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26
Q

What type of cell secretes the GI hormones ?

A

enteroendocrine cells in the mucosa of the epithelium

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27
Q

Between which layers of the GI epithelium does the myenteric plexus lie ?

A
  • longitudinal muscular layer
    myenteric plexus
  • circular smooth muscle layer
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28
Q

Between which layers of the GI epithelium does the submucosal plexus lie ?

A
  • circular smooth muscle layer
    submucosal plexus
  • mucosa
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29
Q

Which 2 plexuses make up the enteric nervous system ?

A
  • myenteric plexus
  • submucosal plexus
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30
Q

Are enteric neurones excitatory or inhibitory ?

A

Both !

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31
Q

What is the main excitatory neurotransmitter released by the enteric NS ?

A

Acetylcholine

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32
Q

Name the 3 main excitatory neurotransmitters released by the enteric NS …

A
  • acetylcholine
  • substance P
  • GRP (gastric releasing peptide)
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33
Q

Name the 2 main inhibitory neurotransmitters released by the enteric NS …

A
  • NO (nitric oxide)
  • VIP (vasoactive intestinal peptide)
34
Q

What is a short reflex?

A

a reflex where all neurones involved are part of the enteric NS

35
Q

What kind of extrinsic nerve fibres synapse with the enteric NS ?

A

preganglionic parasympathetic fibres from the autonomic NS

VAGAL NERVE FIBRES

release the same neurotransmitters as the enteric NS

36
Q

Which type of reflex are parasympathetic nerve fibres involved in, with regards to the GI tract ?

A

Long reflexes

37
Q

Are vagal fibres the efferent or afferent leg of GI tract long reflexes ?

A

both

38
Q

What % of vagal fibres are sensory ?

A

80%

39
Q

What are vago-vagal reflexes an example of ?

A

long reflexes

40
Q

What do sympathetic nerve fibres release that has minor impact on gut motility ?

A

noradrenaline

slight reduction in motility and blood flow

41
Q

Which neurotransmitter reduces motility and blood flow in the gut ?

A

noradrenaline via sympathetic fibres

42
Q

Which GI hormone primarily controls gall bladder function ?

A

CCK

Cholecystokinin

43
Q

How does CCK control gall bladder function ?

A

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

44
Q

What % of enteroendocrine cells are enterochromaffin cells ?

A

90%

45
Q

What type of cells are the main mechano/chemo-sensory cells of the GI tract ?

A

enterochromaffin cells

46
Q

Which neurotransmitter do enterochromaffin cells secrete ?

A

serotonin
5-HT

47
Q

How do enterochromaffin cells show up on a histological stain ?

A

Small dark brown dots (like moles)

48
Q

What % of all serotonin in the body is found in the GI tract ?

A

95% !!

49
Q

What feature of enterochromaffin cells increases their SA ?

A

microvilli

50
Q

What feature of enterochromaffin cells enhances their sensitivity ?

A

microvilli

51
Q

What type of neurone does 5-HT stimulate when released from enterochromaffin cells ?

A

afferent neurones

52
Q

How do neighbouring epithelial cells stop the action of 5-HT released by enterochromaffin cells ?

A

The surrounding membrane contains SERT that removes 5-HT from the junction

53
Q

Why is diarrhoea a side effect of some SSRIs ?

A
  • 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

54
Q

What is a potential cause of IBS that is linked to 5-HT ?

A

SERT mutations, so serotonin action in the GI tract is not terminated sufficiently

55
Q

How does 5-HT stimulate motility/peristalsis in the gut ?

A
  • 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
56
Q

How do toxins and cytotoxic drugs cause vomiting ?

A

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

57
Q

Which type of 5-HT receptors are found on the afferent vagal neurones that extend to the vomiting centre in the medulla ?

A

5-HT3 receptors

58
Q

What is the MOA of antiemetic drugs used in chemotherapy ?

A

5-HT3 receptor antagonists

= target the receptors found on afferent vagal neurones that extend to the vomiting centre in the medulla

59
Q

What physiological change normally instigates vomiting ?

A

retrograde (backwards) peristalsis in the terminal ileum moves contents back towards stomach

60
Q

What is the physiology of vomiting ?

A
  • 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 …

61
Q

What are the 3 main cytotoxic drugs used as antiemetics ?

A
  • 5-HT3 antagonists
  • NK1 antagonists
  • CB1 agonist
62
Q

What are the 2 main drugs used as antiemetics for motion sickness ?

A
  • H1 antagonists (antihistamines)
  • M1 antagonists
63
Q

What are the 2 main drugs used as antiemetics for nausea that is not caused by toxins or motion ?

A
  • D2 antagonists
  • 5-HT3 antagonists
64
Q

which drugs are used to treat the pain of metastatic cancer ?

A

Opiates

65
Q

What are the main side effects of opiates ?

A
  • constipation (main side effect)
  • vomiting (in 30% of patients)
  • dysphoria (agitation)
66
Q

Which pathway do opiates affect that causes nausea ?

A

The vagal afferent neurones to the CTZ (vomiting centre in the medulla)

67
Q

Which are the 3 receptor types that opiates act on in the GI tract ?

A
  • μ opioid receptor
  • δ opioid receptor
  • κ opioid receptor
68
Q

Which opioid receptor is the most important in controlling GI function ?

A

μ opioid receptor

69
Q

How do opiates inhibit synaptic transmission in the gut ?

A
  • 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

70
Q

How do opiates inhibit fluid secretion in the gut ?

A
  • μ receptor activated by opiates
  • activate G proteins which
  • stimulates Gi protein to decrease cAMP
  • causes decreased fluid secretion
71
Q

Which effect of opiates is the main mechanism behind their analgesic properties ?

A

decreased synaptic transmission

- μ receptor activated by opiates
- activates K channels
- inhibits Ca channels
- causes inhibition of synaptic transmission

72
Q

Which action of opiates is the main mechanism behind their inhibitory effect on GI motility ?

A

decreased synaptic transmission

- μ receptor activated by opiates
- activates K channels
- inhibits Ca channels
- causes inhibition of synaptic transmission

73
Q

How do opiates cause constipation ?

A
  • 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

74
Q

How do opioids interfere with gut motility ? (MOA)

A
  • 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

75
Q

What is the impact of opioids on food propulsion through the gut ?

A

opioids reduce forward propulsion of food and cause failure of sphincters to relax

causing constipation

76
Q

What are the 2 main families of endogenous opioids ?

A
  1. Enkephalins
  2. Endomorphins

both present in GI tract

77
Q

What is the function of endogenous opioids in the GI tract ?

A

reduce gut motility

78
Q

Due to their side effect of constipation, what could opioids be used as a drug treatment for ?

A

anti-diarrhoea drugs

79
Q

What is the target receptor of opioids when used as anti-diarrhoea medications?

A

μ opioid receptors

80
Q

What are 2 examples of anti-diarrhoea opioid drugs ?

A
  • Imodium (loperamide)
  • Lomotil (diphenoxylate + atropine)