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GI Week 5 > Laxative, Antidiarrheals, and IBS Drugs > Flashcards

Laxative, Antidiarrheals, and IBS Drugs Flashcards

1
Q

Many of the drugs affecting lower GI function (especially motility) will work by modulating the actions of the enteric nervous system. WHat are the 4 main neurotransmitters involved in motility and water absoprtion regulation (from a pharmacological perspective)?

A

acetylcholine
serotonin
dopamine
enkephalins

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2
Q

In order to either enhance or disrupt the afferent limb of the peristaltic reflex, what NT will need to be altered?

A

5HT

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3
Q

In order to affect interneuron function in the peristaltic reflex, what two NTs need to be altered?

A

dopamine or enkephalins

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4
Q

In order to affect the effector neurons innervating the muscle for peristalsis, what NT needs to be affected?

A

ACh

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5
Q

What effect does 5HT from the enterochromaffin cells have on peristalsis?

A

It promotes peristalsis

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6
Q

What 5 groups of drugs can work at the level of sensory neurons by affecting 5HT?

A 
SSRIs
bulk-forming laxatives
contact cathartics
5HT3 antagonists
5ht4 antagonists
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7
Q

How do SSRIs like fluoxetine, paroxetine and sertraline work in the GI tract?

A
  1. block reuptake of 5HT by the ECL cells
  2. increased 5HT in the synapse activates afferent neuron activity
    3 .increases peristalsis
  3. lessens constipation (diarrhea a side effect)
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8
Q

What are 4 examples of bulk laxatives?

A

dietary fiber
methylcellulose
polycarbophil
psyllium (metamucil)

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9
Q

What is the mechanism of action for the bulk laxatives?

A
  1. they will attract H20 and increase stool mass
  2. icnreases distention of the lumen
  3. increases 5HT release from ECL
  4. Increased afferent activity
  5. increased peristalsis
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10
Q

Which do the bulk laxatives work for: diarrhea or constipation?

A

both actually - they act more as stool stabilizers

in diarrhea they will decrease bowel movement, solidify stools and decreased pain

in constipation they will increased bowel movements, loosen the stool and decrease pain

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11
Q

What are the two factors that limit the use of bulk laxatives?

A
  1. the neurons that generate the peristaltis reflex must be functional
  2. the cause of the constipation musc be known. For examples, if the consiptation is from an obstruction, this could make it a whole lot worse
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12
Q

What are the side effects of the bulk laxatives?

A

allergies
increased flatulence
make obstruction worse

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13
Q

What are the three contact cathartics? well, technically one is a class….

A

anthraquinone derivatives
bisacodyl
castor oil

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14
Q

What is the mechanism of action for the contact cathartics?

A

we don’t really know

it’s maybe direct irritation thorugh contact with the bowel that increases ECL cell release of 5HT to promote peristalsis

maybe same as bulk laxatives

Not sure if they depend on the enteric neurons

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15
Q

What are the three anthaquinones?

A

cascara sagrada
canthron
senna!!!!

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16
Q

Why are bisacodyl and anthraquinones considered laxatives while castor oil is considered a prokinetic?

A

bisacodyl and anthraquinones only work in the large intestine (and are less potenti)

while castor oil acts on both the small and large intestine

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17
Q

What are the side effects of the contact cathartics?

A
  1. you can develop dependency such that person can’t have a BM without it
  2. destroy myenteric plexus wen used long term
  3. pigemtnation of the bowel mucosa = melanosis choli
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18
Q

What are the specific side effects of castor oil?

A
  1. dehydration and electorlytes imbalances because it works so severely and so fast
  2. uterine contractions - so don’t give in pregnancy
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19
Q

What is the 5HT3 receptor antagonist we know?

A

alosetron

note: 3 letters before the S = 5HT3

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20
Q

How does alosetron work?

A
  1. blocks 5HT binding
  2. decreases afferent transmission
  3. decrease peristalsis
  4. decreases diarrhea and also is an antiemetic
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21
Q

Does alosetron have a shorter or longer duration of action compared to other antiemetics?

A

longer

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22
Q

What are the therapeutic uses for alosetron? Why is it a “when all else fails”?

A

diarrhea-predominant IBS when all else fails because it has restricted availability - patient needs to register with compassionate use to get it

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23
Q

What are the side effects for alosetron?

A
  1. constipation (in 30% - 10% will need to stop because of it and .1% will be hospitalized because of it)
  2. 0.3% develop an ischemic colitis that can be fatal
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24
Q

What increases the risk of ischemic colitis with alosetron?

A

use of CYP1A2 inhibitors or substrates = antidepressants!

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25
Q

What are the two 5HT4 receptor agonists?

A

Cisapride and Tegaserod

Note - 2 letters and 4 letters in front of the S (multiples of 4 = 5HT4)

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26
Q

What is the mechanism of action for the 5HT4 receptor agonists?

A

they activate the 5HT4 receptor to increase peristalsis and have a prokinetic effect

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27
Q

Which one is more selective for 5HT4 - Cisapride or tegaserod?

A

Tegaserod

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28
Q

What are the therapeutic uses for Cisapride and Tegasterod?

A

Use when there are no other options - restricted availability

Tegaserod for constipation IBS
Cisapride for diabetic gastroparesis

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29
Q

What is hte main side effect of Cisapride and Tegaserod?

A

cardiovascular toxicity - especially arrhythmias and long QT

but note that 85% of people who get long QT had a pre-existing condition or concomitant administration of cyp3A4 inhibitors

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30
Q

What are the two drugs that are the most effective antidiarrheal drugs?

A

loperamide and diphenoxylate

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31
Q

What NT do loperamide and idphenosylate block?

A

enkephalins

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32
Q

How do loperamide and diphenoxylate work?

A

they inhibit enkephalins

this means you inhibit ACh-triggered contraction and VIP/NO-triggered relaxation necessary for peristalsis

so if they block peristalsis and secretion, they slow down transit time and decrease diarrhea

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33
Q

Why is loperamide available OTC but diphenoxylate is not?

A

loperamide can’t cross the BBB so it has little potential for addiction

DIphenoxylate can

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34
Q

What do they add to diphenoxylate to help avoid addiction?

A

atropine

it will have a synergistic effect and the side effects of atropine are terrible, so people don’t want to abuse it

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35
Q

What are the potential side effects of loperamide and diphenoxylate?

A
  1. abdominal cramps
  2. toxic megacolon if the patient has ulcerative colitis
  3. high dose of diphenoxylate can cause euphoria and physical dependance
36
Q

What two mu receptor antagonists can you use to offset the constipation caused by opiate analgesics? Why dont they block the analgesic effect?

A

Alvimopan
Methylnatroxone

they don’t cross the BBB

37
Q

Which one - Alvimopan or Methylnatroxone – is used in a hospital setting and which is used long term in palliative care? Why?

A

Alvimopan has an increased risk of MI, so it’s only used in hospitalized patients that can be monitored closely

Methylnatroxone is used longterm in palliative care

38
Q

What are the two Dopamine 2 receptor antagonists? Which is more commonly used?

A

Domperidone (not readily available here - crosses BBB)

Metoclopramide (readily available in US)

39
Q

What is the mechanism of action for metoclopramide and domperidone?

A

they are cholinomimetics

They inhibit dopamine inhibition on ACh, thus potentiation ACh action in the gut

this increases motility in the entire gut (prokinetic)

40
Q

What is the main therapeutic use for domperidone (compassionate use) and metoclopramid?

A

They will treat constipation in cases with impaired GI motility - especially decreased gastric emptying from vagotomy or diabetic gastroparesis

41
Q

What is the other use for metoclopramide?

A

an antiemetic used to treat persistent hiccoughs

42
Q

What are the side effects for domperidone and metoclopramide?

A

somnolence, nervousness, agitation, anxiety
dystonia, parkinsonism, tardive dyskinesia (which can be permanent!)

can increase prolactin release leading to impotence in males and menstrual disorders and galactorrhea in females

43
Q

In general, drugs directly affecting cholinergic (ACh) nerges are generally NOT used to treat diarrhea and constipation. WHat are the two exceptions?

A

tricyclic antidepressants and atropine

44
Q

How do the triyclic antidepressants work in the gut?

A
  1. decrease reuptake of NE from postganglionic sympathetic neurons
  2. increase activation of alpha2 receptors of presynaptic terminals
  3. decreases the cholinergic post-ganglionic parasympathetic nerve activity
  4. decrease ACh release
  5. decrease peristalsis and motility
  6. lessens diarrhea (constipation a side effect)

note - also blocks reuptake of dopamine, so it increases D2 activity which decreases ACh released…same general mechanism

45
Q

How does atropine work in the gut?

A

direct antimuscularic - blocks ACh to decrease peristalsis

46
Q

What class of drugs will stimulate the motilin receptors on smooth muscle? What will this trigger?

A

macrolide antibiotics like erythromycin

will trigger activation of the migrating motor complex

47
Q

Why is use of the macrolide antibiotics to treat constipation controversial?

A

it might increase ABx resistance among the GI bugs

48
Q

Newer treatments for diarrhea and constpiation are directed toward the transporters responsible for chloride secretion in the colon which are…

A

CIC2 and CFTR

49
Q

What drug will stimulate the CIC2 channel to increase Cl secretion and decreased constipation?

A

Lubiprostone

50
Q

What are the the therapeutic uses for Lubiprostone?

A

chronic constipation

constipation-predominant IBS

51
Q

What are the side effects for lubiprostone?

A

It’s poorly absorbed, so there are few systemic effects - can have diarrhea, nausea and headache

in animals noted to increase fetal loss, so it’s a class C drug - don’t give to pregnant women

52
Q

What drug will activate guanylate cyclase to increase cGMP activation of the CFTR?

A

Linaclotide

53
Q

WHat are the side effects of linaclotide?

A

diarrhea, increased maternal death in animals( (don’t use in pregnant women), and increased death in juvenile mice (don’t use in pediatric populations)

54
Q

What drug is a CFTR inhibitor?

A

Crofelemer

55
Q

Exaplain the mechanism of action for Crofelemer?

A

it causes voltage independent inhibition of CFTR, which decreases Cl secretion and thus decreases Na and H20 secretion to promote firmer stools

56
Q

What are the therapeutic uses for Crofelemer? Hint: it’s very specific….

A

diarrhea due to anti-HIV drug treatments (the NRTIs and protease inhibitors cause terrible diarrhea)

57
Q

What is octreotide?

A

a somatostatin analogue

58
Q

What is the mechanism of action for octreotide?

Specifically what is its effect on motility?

A

it acts at somatostatin receptors to decrease fluid secretion (among other things)

At low doses it will increase motility and at high doses it will decrease motility

59
Q

So what type of dose o we want for an antidiarrheal effect with octreotide?

A

high doses

60
Q

What is the off label related therapeutic use for octreotide?

A

it’s off label for severe diarrhea caused by dumping syndrome, short bowel syndrome, vagotomy and AIDS treatment

61
Q

Octreotide has many side effects, including…

A

impaired pancreatic secretion, so decreased fat absorption and fat soluble vitamin deficiencies

decreased GI motility depending on dose - nausea, abdominal pain, flatulence

decreased gall bladder contractioiy - gall stones in 50% and rarely acute cholecystitis

problems with insulin/glucagon balance = hypo or hyperglycemia

hypothyeoiridsm

bradycardia

62
Q

For bismuth subsalicylate, which is the improtant bit in the stomach andw hich is the important bit in the colon?

A

the bismuth is important for the stomach while the subsalicylate is important in the colon

63
Q

What is the mechanism of action for the salicylate?

A

It decreases prostaglanding and chloride secretion in the large intestine, so helps treat diarrhea

also has some antimicrobial effects and can bind enterotoxins

64
Q

What is the main use for bismuth subsalicylate in this scenario?

A
  1. PREVENTION of diarrhea (THE ONLY ONE!)
  2. treatment of traveller’s diarrhea

note - not as effective as the opiates once the diarrhe ahas already started

65
Q

What are the main side effects of bismuth subalicylate?

A

blackening of stool and tongue

salicylate toxicity with tinnitus and acid/base disturbances

66
Q

What are the four osmotic cathartics?

A

Lactulose
Magensium hydroxide
Sodium phosphate
Polyethylene Glycol Electrolyte Solution

67
Q

What is the general mechanism of actino for the osmotic cathartics?

A

like the name suggests….

they are not absorbed, so the lumen pulls water in by osmosis

68
Q

What is the therapeutic use for the osmotic cathartics?

A

constpiation - especially when the enteric nervous system is disrupted so you can’t increase peristalsis

69
Q

What is the particular therapeutic use for lactulose?

A

it will decrease plasma ammonia concentration, so it’s used in portal systemic encephalopathy

70
Q

If absorbed systemically, all the osmotic laxatives can cause what?

A

intravascular volume depletion and electrolyte imbalances like hyperphosphatemia, hypocalcemia, hypernatremia and hypokalemia (arrythmias)

71
Q

Bottom line is that the osmotic cathartics are safe in the vast majority of patients, but who should you use them in with caution?

A

patients whoa re frail, elderly, have renal insufficnecy or have significant cardiac disease

72
Q

Why does lactulose cause severe cramps, flatulence and abodminal discomfort?

A

it’s just a large sugar that can’t be broken down except by colonic bacteria, so you essentially get the same symptoms as you do in a lactose intolerance

73
Q

What are the two bile acid binding resins we know?

A

cholestyramine

colestipol

74
Q

What is the mechanism of action for the bile acid binding resins in this context? Also need to state the therapeutic use for this to make sense…

A

If someone has decreased reabsorbtion of bile salts dur to crohns disease or resection of the terminal ileum, they will likely have a secretory diarrhea

the bile acid binding resins will bind the unobsorbed bile acids to deal with this problem, decreasing H2O secretion into the lumen and treating the diarrha

75
Q

What are the side effects of the bile acid resins?

A

lots of blating, flatulence, constipation, fecal impaction - makes them miserable unfortunately

can also impair the absorption of other drugs and fat soluble vitamins

76
Q

What are the two stool softeners we know?

A

Docusate and mineral oil

77
Q

How does docusate work? Mineral oil?

A

Docusate is basically a surfactant soap that will make water and fat lubricate the stool

mineral oil just lubricates the stool directly

78
Q

What are the therapeutic uses for docusate and mineral oil?

A

they are considered the mildest of the laxatives, so their use is widespread

just note they don’t work on everything and should not be used in cases of undiagnosed a bdominal pain or intestinal pathology

79
Q

What’s the bad side effect for mineral oil?

A

it can result in lipid pneumonitis if aspirated

also, long term use can cause fat soluble vitamin deficiencies

80
Q

Wha tare the three types of prokinetic agents (i.e. drugs that increase motility through the ENTIRE GI tract)?

A
  1. D2 receptor antagonists like metochlopramide
  2. Macrolides like erythromycin
  3. 5HT4 agonists like cisapride
81
Q

In what cases are the prokinetic agents particularly helpful in general?

A

impaired gastric emptying and constipation due to diabetic gastroparesis

82
Q

When should you NOT use antidiarrheals if someone has diarrhea?

A

if the diarrhea is bloody, if the patient has high fever or signs of systemic toxicity

it’s likely a bacterial infection and blocking the diarrhea could just make it worse

83
Q

What are the 5 classes of antidiarrheal?

A
  1. opiates (most effectives)
  2. bile acid binding resins
  3. Octreotide
  4. Biismuth Subsalicylate
  5. Crofelemer
84
Q

What should prescription of laxatives be secondary to?

A

dietary modifications, increased fluid intake and physical activity

85
Q

What are the four general classes of laxatives?

A

Cl channel activators
stool softeners
bulk forming laxatives
contact cathartics

86
Q

What consideration comes up with latencty to effect for the laxatives?

A
  1. the mild effects with long latency drugs are laxatives - stool softeners, Cl activators and bulk forming - that take 1-3 days to work
  2. the Intermediate latency to effect produce soft semi-solid stool in about 6-8 hours (the contact cathartics)
  3. Strong effect with short latency comes from the osmotic cathartics and castor oil - cause watery evacuation in 1-3 hours
87
Q

For IBS treatment….

Which would be better for diarrhea predominant - alosetron or tegaserod?

A

alosetron - the 5HT3 antagonist that slows peristalsis

tegaserod is a 5HT4 agonist that is used in treating constipation-predominant

GI Week 5 (6 decks)

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