Gi System- Antiemetics By Maloney

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GI System- Antiemetics by Maloney

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GI System- Antiemetics by Maloney

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Digoxin

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can give you nausea and vomiting by activating the chemoreceptor trigger zone, then the vomit center

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Motion sickness.. how does it get to the vomit center? What can you do to prevent motion sickness?

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vestibular apparatus -> H1, M receptors (for ACh and histamine)-> cerebellum -> vomit center

so you can use muscarinic and/or H1 blockers to stop motion sickness
(not H2 blockers b/c it's involved in the stomach for acid production)

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Postoperative Nausea and Vomiting...causes and pathway to the vomit center?

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Surgery:
Gut (5-HT3 receptors on vagal afferent fibers where serotonin binds) -> CTZ, NTS (5-HT3, D2, NK1 receptors (for substance P)) -> Vomit center

Opioids, Anesthetics:
Activate CTZ (b/c no BBB)

Opioids, Surgery, Movement:
Vestibular apparatus (H1, M) -> Vomit Center

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What type of drugs will be effective in preventing PONV?

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Vestibular apparatus: H1, M

Gut: 5-HT3

CTZ, NTS: 5-HT3, D2, NK1

and corticosteroids

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Radiation or Chemotherapy induced Nausea and vomiting

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Cellular damage releases NT such as serotonin which causes damage to the gut which bind to 5-HT3 receptors on vagal afferents

Antineoplastic agents as well as the NTs can go directly to the brain (CTZ, NTS) since there's no BBB

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What type of drugs will be effective in preventing chemotherapy-induced nausea and vomiting?

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Gut: 5-HT3

CTZ, NTS: 5-HT3, D2, NK1, CB1 (cannabinoid receptors)

and corticosteroids

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What is the the big drug(s) that we use for motion sickness?

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muscarinic receptor antagonist:
Scopolamine
*muscarinic is the main thing to block to prevent motion sickness

Histamine H1 Receptor Antagonists:
-Dimenhydrinate (does H1 and M)
-Meclizine
-Promethazine (Phenergan)-> for severe

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Clinical use of Scopolamine?

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Histamine H1 Receptor Antagonists:
-motion sickness
-PONV

Note: Second generation antihistamines do not cross the BBB. Therefore they are not sedating, and are not antiemetic.

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Dopamine Receptor Antagonists are also? MoA?

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Anti-psychotics.

Phenothiazines:
-Prochlorperazine

MoA:
-Block dopamine receptors (D2) in the CTZ and NTS to prevent nausea and vomiting
-Block D2 receptors in the GI tract to prevent the inhibition of intestinal motility associated with NV

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Clinical use for Prochlorperazine?

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-Postoperative nausea and vomiting
-Radiation-induced nausea and vomiting
-Chemotherapy-induced nausea and vomiting
**Low emetogenic potential
-Nausea and vomiting caused by toxins, various drugs or diseases (e.g. migraine)

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Why do they have limited effect on chemotherapy induce nausea and vomiting?

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D2 receptor is knocked out, but the 5-HT3 receptors are still there in the CTZ and the gut. So you need to knock out the 5-HT3 receptors in the gut in order to treat cisplatin induced NV.

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Will prochlorperazine be useful in preventing motion sickness?

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no. doesnt block H1 or M receptors. very little if any effect.

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Note about Droperidol. What is the black box warning?

(not spoken about in class)

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Black box warning that it prolongs the QT interval and may cause torsades de pointes

It has gone from a low-cost, first-line treatment for PONV that was considered safe, to a high-cost (when monitoring is used), second- or third-line treatment of questionable safety.

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Metoclopramide (Reglan) MoA..what happens if you take this at high doses? clinical uses?

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MoA:
-Blocks D2 receptors in the CTZ and NTS
-High doses also block 5-HT3 receptors in the CTZ, NTS and the GI tract
-Enhances gastric emptying, which is believed to minimize stasis that precedes vomiting

Clinical Use:
Chemotherapy-induced nausea and vomiting – High dose
Radiation-induced nausea and vomiting – High dose
Post operative nausea and vomiting – Low dose -> DOESNT WORK

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Would metoclopramide be useful for motion sickness?

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no, doesnt effect H1, M receptors.

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Metoclopramide (Reglan) adverse effects

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Extrapyramidal reactions:
-Blocks D2 receptors in the CNS
-Especially with high doses
-Tardive dyskinesia
(parkinsons like movement disorders)

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5-HT3 Receptor Antagonists

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"-setron"

Ondansetron (Zofran)
Granisetron (Kytril, Sancuso)
Dolasetron (Anzemet)
Palonosetron (Aloxi)

they block serotonin recptors

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5-HT3 Receptor Antagonists clinical use:

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Chemotherapy-induced nausea and vomiting
-Prevents acute NV (within 24 h)
-Little effect on delayed NV (1-5 days) when used as monotherapy

Acute is 5-HT
Delayed is substance P

Anticipatory: Conditioned response that involves the cerebral cortex
Acute: Occurs within few minutes to several hours after chemotherapy and is gone by 24 hours
Delayed: Usually occurs between 1 and 5 days after chemotherapy

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5-HT3 Receptor Antagonists clinical use:

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Chemotherapy-induced nausea and vomiting
-Prevents acute NV (within 24 h)
-Little effect on delayed NV (1-5 -days) when used as monotherapy.
-Except palonosetron works better for delayed NV

-Radiation-induced nausea and vomiting
-Postoperative nausea and vomiting
-Not effective for motion sickness

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5-HT3 Receptor Antagonists pharmacokinetics

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Half life ranges from 3 to 9 hours
Ondansetron
Granisetron
Dolasetron

Half life of about 40 hours
Palonosetron

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Adverse Effects

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Constipation
Diarrhea
Headache
Rash and hypersensitivity reactions
Prolong PR and QT interval, widen QRS
-Rarely lead to cardiac arrhythmias

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What is the advantage of using ondansetron vs metoclopramide?

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less side effects because it doesn't block D2 receptors.

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5-HT3 Receptor Antagonists clinical use:

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Chemotherapy-induced nausea and vomiting
-Prevents acute NV (within 24 h)
-Little effect on delayed NV (1-5 days) when used as monotherapy

Acute is 5-HT
Delayed is substance P

Anticipatory: Conditioned response that involves the cerebral cortex
Acute: Occurs within few minutes to several hours after chemotherapy and is gone by 24 hours
Delayed: Usually occurs between 1 and 5 days after chemotherapy

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5-HT3 Receptor Antagonists clinical use:

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Chemotherapy-induced nausea and vomiting
-Prevents acute NV (within 24 h)
-Little effect on delayed NV (1-5 -days) when used as monotherapy.
-Except palonosetron works better for delayed NV

-Radiation-induced nausea and vomiting
-Postoperative nausea and vomiting
-Not effective for motion sickness

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5-HT3 Receptor Antagonists pharmacokinetics

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Half life ranges from 3 to 9 hours
Ondansetron
Granisetron
Dolasetron

Half life of about 40 hours
Palonosetron

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Adverse Effects

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Constipation
Diarrhea
Headache
Rash and hypersensitivity reactions
Prolong PR and QT interval, widen QRS
-Rarely lead to cardiac arrhythmias

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What is the advantage of using ondansetron vs metoclopramide?

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less side effects because it doesn't block D2 receptors.

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Substance P/neurokinin 1(NK1) receptor antagonists

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Aprepitant (Emend)
Fosaprepitant (Emend for Injection)
-IV form converted to aprepitant

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clinical use

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Chemotherapy-induced nausea and vomiting
-Prevents acute and delayed nausea and vomiting
-In combination with high dose metoclopramide or a 5-HT3 antagonist plus dexamethasone

Postoperative nausea and vomiting

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Corticosteroids..whats the big one? clinical use?

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Dexamethasone
Mechanism of action is unknown
A local inflammatory reaction may influence vagal nerve endings in the gut to trigger emesis?

-Combined with other agents (e.g. 5-HT3 antagonist or high dose metoclopramide) to improve efficacy in preventing chemotherapy-induced nausea and vomiting
-Monotherapy or combination therapy for delayed chemotherapy-induced nausea and vomiting
-Post operative nausea and vomiting

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Cannabinoids agents, moa,

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Dronabinol (Marinol)
Nabilone (Cesamet)
"-bilon-"

Unknown
May bind to CB1 subtype of cannabinoid receptor on the CTZ

Chemotherapy-induced nausea and vomiting
-Not adequately controlled by other drugs

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Adverse Effects

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Dysphoria
Hallucinations
Sedation
Vertigo
Dry mouth
Disorientation

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Treatment of CINV overview

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D2- minimal to low
5-HT3- minimal to high
Dexamethasone- min to high
NK1- mod to high

need 5-HT3, dex, and NK1 together for moderate and high