14 - GI Pharmacology II Flashcards by Andrea Okas

What are the common neurotransmitters that affect gastric motility?

Serotonin (inc.)
Dopamine (dec.)
Acetylcholine (inc.)
Motilin (inc.)

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How does serotonin induce gastric motility?

By inducing the

release of acetylcholine by neurons onto gastrointestinal smooth muscle (contraction of gastric smooth muscle)

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How does dopamine affect gastric motility?

By activating presynaptic receptors to decrease the firing of ENS neurons, therefore decreasing gastric motility

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How does acetylcholine affect gastric motility?

By activating muscarinic receptors to induce contraction of gastrointestinal smooth muscle

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How does motilin affect gastric motility?

Promotes gastric motility through activation of motilin receptors located on gastrointestinal smooth muscle

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What are the four prokinetic agents used to increase gastric motility?

1 - Metoclopramide
2 - Bethanechol
3 - Neostigmine
4 - Erythromycin

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What is the mechanism of action and use of metoclopramide?

D2 antagonist (blocks the dopamine receptor - remember dopamine slows down gastric motility)
Used to treat GERD, impaired gastric emptying, dyspepsia and is used as an antiemetic

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What are the adverse effects of metoclopramide?

CNS (restlessness, drowsiness, insomnia, anxiety)

- Altered motor function (Parkinsonian symptoms - because it can cross the BBB)

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What is the mechanism of action and use of bethanechol?

M3 anonist (stimulates ACh receptor

- Used to treat GERD and gastroparesis

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What are the adverse effects of bethanechol?

Cholinergic side effects

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What is the mechinism of action and use of neostigmine?

AChE inhibitor

- Used to treat non-obstructive urinary retention and abdominal distention

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What are the adverse effects of neostigmine?

Cholinergic side effects

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What is the mechanism of action and use of erythromycin?

Motilin receptor agonist (increases the effects of motilin)
Used to treat gastroparesis

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What are the adverse effects of erythromycin?

Erythromycin mediated side effects

- Antibiotic use can cause diarrhea

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What are laxatives commonly used to treat?

Constipation (infrequent evacuation of the feces)
Minimizing strain during defecation following cardiothoracic surgery
Clear GI tract before endoscopy

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What are the main causes of constipation?

Hormone secreting tumors that decrease motility
Presence of toxins
Various disease states
Diet, stress, exercise, etc.

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There are 8 laxatives you need to know about, which can be grouped into either physical-induced laxatives (4) and receptor-induced laxatives (4)

Physical-induced laxatives

Methylcellulose (bulk-forming)
Glycerin (surfactant)
Lactulose (osmotic)
Senna (stimulant)

Receptor-induced laxatives

Tegaserod (serotonin agonist)
Lubiprostone (chloride channel activator)
Methylnaltrexone (mu-opioid receptor antagonist)
Alvimopan (mu-opioid receptor antagonist)

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For the physical-induced laxatives, how good is the absorption?

Poor

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For the physical-induced laxatives, what is the use?

Constipation
Minimize straining
Prior to surgical or endoscopic procedure

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How does the bulk-forming methylcellulose work?

Non-digestible fiber forms a gel-like substnace in the intestine and causes distention of the GI tract which induces peristalsis

Their adverse effect is gas and bloating

How do surfactant stool softeners like glycerin work?

The stool is penetrated by water and lipids which lubricates the hardened stool and coats it for easy passage

Their adverse effect is nutrient malabsorption

How do osmotic laxatives like lactulose work?

Induce a change in osmotic pressure inducing water absorption back into the lumen of the colon

Their adverse effect is gas and electrolyte flux

How do stimulant laxatives like senna work?

They stimulate the ENS to induce peristaltic contractions

Their adverse effect is GI irritation

Describe the serotonin agonist tegaserod

A 5-HT4 partial agonist
Poor absorption (10%)
Used to treat chonic idiopathic constipation
NOT available for general use (GI and cardiovascular adverse effects)

Describe the chloride channel activator lubiprostone

- It is a prostaglandin derivative - Poor absorption - Used for chronic constipation - Stimulates chloride ion secretion and thus fluid secretion by the large intestine - Adverse effects of nausea/vomiting and diarrhea

Describe the mu-opioid receptor antagonists (methylnaltrexone and alvimopan)

Block peripheral mu-opiod receptors **Peripheral is the key here"* These agents do not cross the BBB, so they are able to block the constipating effects of opioids without blocking the intended therapeutic effect in the CNS

What is methylnaltrexone mainly used for?

To alleviate opiod-induced constipation during palliative care The adverse effects are abdominal pain, gas, nausea and diarrhea

What is alvimopan mainly used for?

Postoperative ileus (obstruction) in hospitalized patients with bowel resection Adverse effects are similar to methylnaltrexone but include MI, so it can only be used for SHORT TERM use (7 days)

What are the 5 drugs you need to know which have an anti-diarrheal effect?

``` 1 - Loperamide 2 - Diphenoxylate 3 - Bismuth subsalicylate 4 - Cholestyramine 5 - Octreotide ```

Which two anti-diarrheal agents are opioid agonists?

Loperamide and diphenoxylate

What is loperamide used to treat?

AKA Imodium Diarrhea from IBS The only adverse effect is constipation (it is otherwise very safe)

What is diphenoxylate used to treat?

AKA lomotil Diarrhea Adverse effects are CNS and atropine effects

How does bismuth subsalicylate work?

AKA pepto bismal Antidiarrheal effects occur through inhibition of prostaglandin synthesis in the intestine (this contrasts what happens in the stomach) Also, through the ability of bismuth subsalicylate to absorb toxins secreted by bacteria Can develop salicylate toxicity at high doses

What is bismuth subsalicylate particularly helpful in treating?

Traveler's diarrhea

How does cholestyramine work?

It is a bile salt resin which are used to treat diarrhea caused by malabsorption of bile salts by the ileum in cases of Crohn's disease or resection of the ileum They reduce osmotic pressure which is caused by unabsorbed bile salts Adverse effects include bloating, gas, constipation, fecal impaction and impaired fat absorption

How does octeotride work?

It is a peptide that activates the somatostatin receptor in the GI tract to increase fluid absorptionand decrease motility so there is more time to absorb water Useful in treating secretory diarrhea Adverse effects include impaired pancreatic secretion, decreased motility, decreased gall bladder contraction, glucose homeostasis

What is an emetic response?

Vomiting

What can initiate an emetic response?

- Sensory stimulation - Blood-borne emetics - Gastrointestinal irritants

What part of the brain initiates emesis?

Medulla

What receptors mediate the emetic response?

- Serotonin (5-HT) - Dopamine (D) - Muscarinic (M) - Histamine (H) - Neurokinin (NK)

Why are these receptors relevant?

Simply antagonizing these receptors can block or blunt an emetic response They are all pro-emesis so if you block them, you stop vomiting

What are the six receptor antagonists that are anti-emetics and what receptor do they block?

``` 1 - Ondansetron (5-HT) 2 - Scopolamine (M1) 3 - Metoclopramide (D2) 4 - Dimenhydrinate (H1) 5 - Aprepitant (NK1) 6 - Prochlorperazine (M1, D1, H1) ```

Which of the anti-emetic receptor antagonists are used to treat motion sickness?

- Scopolamine (patch behind the ear) | - Dimenhydrinate (AKA dramamine - causes drowsiness)

Which of the anti-emetic receptor antagonists are used to treat chemo, radiation and post-op vomiting?

- Ondansetron - Metoclopramide - Aprepitant

Which is used to treat severe vomiting?

Prochlorperazine It is the end all cure all... Last resort that you use when all else fails

What other sites in the CNS would be useful targets for anti-emetic therapy?

- GABAergic neurons - Cannabinoid receptors - Glucocorticoid receptors

What are these alternative anti-emetic drugs used for?

Mostly for chemotherapy vomiting

What are the three agonists for anti-emetic therapy?

1 - Lorazepam (GABA agonist, anxiety) 2 - Nabilone (Cannabinoid agonist) 3 - Dexamethasone (glucocorticoid agonist, post-op)