EXAM #1: GI PHARMACOLOGY II Flashcards by Mohammed Al-Amri

What is the role of 5-HT in GI motility?

1) 5-HT stimulates gastric motility by inducing the release of ACh from neurons on the gastric smooth muscle
2) Plays a role in relaying sensory information from the gut to CNS

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What is the role of ACh in GI motility?

ACh binds muscarininc receptors to INCREASE GI motility

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How is ACh metabolized?

AChE

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What is the role of DA-2 in GI motility?

Dopamine activates pre-synatic receptors in ENS neurons to decrease neuronal firing
This leads to a decrease in GI motility

Specifically, pre-synaptic DA-2 agonism negatively regulates release of ACh on gastric smooth muscle

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What is the physiologic outcome of DA-2 agonism?

Decreased motility

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What is the physiologic outcome of DA-2 antagonism?

Increased motility

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What is the role of Motilin in GI motility?

Promotion of GI motility in the UPPER GI tract

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What are “prokinetic agents?”

Agents that increase GI motility

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List the Prokinetic agents.

Metoclopramide
Bethanechol
Neostigmine
Erythromycin

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What is the mechanism of action of Metoclopramide?

DA-2 Antagonist

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What are the indications for Metoclopramide?

1) GERD
2) Impaired gastric emptying
3) Dyspepsia
4) Antiemetic

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What are the adverse effects of Metoclopramide?

CNS

Restlessness
Drowsiness
Insomnia
Anxiety

Altered Motor Function
- PD-like symptoms

This drug crosses the BBB; thus, as a DA-antagonist, it can cause PD-like symptoms.

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What is the mechanism of action of Bethanecol?

M3 agonist

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What are the indications for Bethanecol?

1) GERD

2) Gastroparesis

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What are the adverse effects of Bethanecol?

Cholinergic side effects

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What is the mechanism of action of Neostigmine?

AChE inhibitor

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What are the indications for Neostigmine?

NON-OBSTRUCTIVE

1) Urinary retention
2) Abdominal distension

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What are the adverse effects of Neostigmine?

Cholinergic side effects

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What is the mechanism of Erythromycin?

Motilin receptor agonist

This is an antibiotic. One of the side effects of many abx is diarrhea. Here the reason that this drug causes diarrhea is b/c it is a motilin receptor agonist.

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What is the indication for Erythromycin?

Gastroparesis

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What are non-pharmacologic methods to treat constipation?

1) Increase water intake
2) Increase fiber intake
3) Exercise

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What is a “bulk-forming” laxative?

Ingestion of fiber that CANNOT be digested and absorbed
Fiber retains water in the lumen of the GI tract

Bulk-forming agents will form a large clump/bolus that will induce a mass peristaltic contraction. Water retention with fiber will make the movement easier.

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What does a bulk-forming laxative need to be taken with?

WATER–things can be made worse without water

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What is the prototypical bulk forming agent?

Methylcellulose

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What is the mechanism of action of a stool-softener?

1) May literally soften stool | 2) May "coat" and cause stool to "fall out"

What is the prototypical stool softener?

Glycerin

What is an osmotic laxative?

Drugs that induce changes in osmotic pressure with non-absorb-able sugars and salt

What are the prototypical osmotic laxative agents?

Lactulose

What are the mechanisms of "stimulant" laxatives?

These are laxatives that generally stimulate the ENS, and may also: 1) Induce "leaky" mucosa 2) Inhibiting Na+ uptake by the gut

What is the prototypical stimulant laxatives?

Anthraquinone derivatives such as aloe and SENNA

What are the indications for laxatives?

1) Constipation 2) Minimize straining post operatively 3) Prior to surgical/ endoscopic procedure

What is the adverse effect of bulk forming agents?

Gas and bloating that can lead to abdominal discomfort

What is the adverse effect seen with surfactants/ stool softeners?

Nutrient malabsorption Coating of the GI tract and absorptive surface on a chronic basis will lead to malabsorption.

What is the adverse effect of stimulant laxatives?

General GI irritation

What are the adverse effects of the osmotic laxatives?

- Gas/ bloating | - Electrolyte flux

How can 5-HT receptors be targeted for therapeutic action as a laxative? What is the secondary advantage of this mechanism?

1) Activation of 5-HT4 receptors will promote NT release in ENS, resulting in motility 2) Activation will also decrease firing of extrinsic sensory neurons to the CNS i.e. block pain Some of the NTs include ACh

What is the prototypical 5-HT4 receptor agonist?

Tegaserod

What is a CIC-2 channel?

Chloride Ion Channel 2

Describe how activation of CIC-2 channels can function as laxatives.

- Cl- channel - Cl- into the lumen, Na+ and water follow As a result, stool will soften and motility will be stimulated

What type of laxative can be used to treat opoid induced constipation?

Mu-opoid receptor ANTAGONIST These drugs do NOT cross the BBB; thus, there is antagonism of mu-opoid receptors in the gut to prevent constipation, but opoid analgeisa will NOT be affected.

What is the prototypical CIC-2 agonist?

Lubiprostone

What are the prototypical mu-opoid receptor antagnoist?

Methylnaltrexone | Alvimopan

What is the indication for Tegaserod?

Chronic idiopathic constipation

What is the inidication for Lubiprostone?

Chronic constipation

What are the adverse effects of Lubiprostone?

Nausea Vomiting Diarrhea

What is the indication for Methylnaltrexone?

Opoid-induced constipation during palliative care

What are the adverse effects of Methylnaltrexone?

Abdominal pain Flatulence Nausea Diarrhea

What are the indications for Alvimopan?

Post-operative ileus in hospitalized patients with bowel resection

What is the adverse effect associated with Alvimopan? What are the treatment indications?

Myocardial infarction; thus, only use on a SHORT TERM bases i.e. less than 7 days

What is the general pharmacological strategy to treat diarrhea?

1) Treat the underlying cause | 2) Anti-diarrheal agent

What type of opoid durg is used as an anti-diarrheal?

Mu-opoid AGONIST

How do opoids alter GI smooth muscle?

Activation of opoid receptors in the GI system generally SLOW motility by: 1) Decreasing peristalsis 2) Increasing segmental (mixing) contractions 3) Increasing internal anal sphincter tone 4) Decreasing perception of GI distension

Describe Bismuth Subsalicylate's mechanism of action as an anti-diarrheal.

1) Thick substance that can absorb GI toxins 2) Salicylate DECREASES intestinal PG secretion - This leads to a decrease in smooth muscle contraction and secretion of water Note that this is in CONTRAST to what is seen in the STOMACH, where Bismuth Subsalicylate INCREASES PG synthesis

What is the mechanism of action of bile salt binding resins as antidiarrheals?

1) Bind bile salt 2) Excreted into the feces Bile is reabsorbed in the ileum. Chorn's disease or ileal resection can prevent proper absorption of bile salts. Excess bile salts in the lumen cause osmotic diarrhea. Thus, excretion of bile salts by binding to resins prevents diarrhea.

What is Octreotide?

- SOMATOSTATIN agonist - Peptide that is similar in structure to SOMATOSTATIN that: 1) Decreases GI motility 2) Increases fluid absorption

What are the prototypical opoid agonists used as anti-diarrheals?

Loperamide | Diphenoxylate

What are the adverse effects of Loperamide?

Constipation

What are the adverse effects of Diphenoxylate?

CNS effects Atropine effects Note that this drug has more CNS effects compared to Loperamide. Thus, it is given in conjunction with atropine to deter abuse.

What is the mechanism of action of Cholestyramine?

This is a bile acid resin that binds bile salts and facilitates their fecal elimination

What is the indication for Cholestyramine?

Impaired bile salt-absorption mediated diarrhea, which can be seen in: 1) Chron's Disease 2) Ileal resection

What are the adverse effects of Cholestyramine?

- Bloating - Flatulence - Fecal impaction - Impaired fat absorption/ fat-soluble vitamin absorption

What is the mechanism of action of Octreotide?

Somatostatin receptor agonist that: 1) Increases fluid absorption 2) Decreases GI motility

What are the indications for Octreotide?

Secretory diarrhea

What are the adverse effects of Octreotide?

1) Impaired pancreatic secretion 2) Decreased GI motility causes nausea and pain 3) Decreased gallbladder contraction 4) Impaired glucose homeostasis

What are the receptors that regulate the emetic response?

``` H1 M1 D2 NK1 5-HT3 ```

What is the general strategy of antiemetic drugs?

Antagonism of the various receptors involved in the emetic response

List the antiemetic drugs.

``` Ondansetron Scopolamine Metoclopramide Dimenhydrinate Aprepitant Prochlorperazine ```

What emetic receptor is antagonised by Ondansetron?

5-HT3

What emetic receptor is antagonised by Scopolamine?

What emetic receptor is antagonised by Metoclopramide?

What emetic receptor is antagonised by Dimenhydrinate?

What emetic receptor is antagonised by Aprepitant?

NK1

What emetic receptors are antagonised by Prochlorperazine?

M1 D2 H1

Which two antiemetics are used specifically for motion sickness? What receptors do they antagnoize?

Scopolamine (M1) | Demenhydrinate (H1)

What antiemetic is used for emesis caused by: 1) chemotherapy, 2) postoperative, 3) post-radiation?

Ondansetron

What antiemetic is indicated for chemo and radiation induced nausea and vomiting?

Meoclopramide

What anti-emetic is used for nausea and vomiting associated with chemotherapy?

Aprepitant

What anti-emetic is used for severe nausea and vomiting, when other anti-emetic have not worked? Why?

Prochlorperazine b/c it blocks M1, D1, and H1 receptors (the most)

What are the indirect antiemetic agents?

These are agents that will increase NT release to have a decrease in the emetic response

What are the three general mechanisms of indirect antiemesis?

1) GABA agonist 2) Cannabinoid agonist 3) Clucocorticoid agonist

What is the GABA agonist used as an antiemetic?

Lorazepam

What is the Cannabinoid agonist used as an antiemetic?

Nabilone

What is the Clucocorticoid agonist that is used as an antiemetic?

Dexamethasone