A-32. Antiemetic drugs. Prokinetic agents. Drugs for irritable bowel disease (IBS).

Question 1

Antiemetic drugs (MOA & list)

Answer 1

1. H1 antagonists:
   a. Diphenhydramine
   b. Promethazine
   c. Dimenhydrinate
2. Antimuscarinics:
   a. Scopolamine
3. D2 antagonists:
   a. Chlorpromazine
   b. Thiethylperazine
   c. Haloperidol
   d. Metoclopramide
   e. Domperidone
4. 5HT3 antagonists:
   a. Granisetron
   b. Palonosetron
   c. Ondansetron
5. Neurokinin-1 receptor antagonists:
   a. Aprepitant
   b. Fosaprepitant
6. CB1 agonists:
   a. Dronabinol
   b. Nabilone
7. Others:
   a. Dexamethasone - corticosteroid; combined with
   5-HT3 atg or D2 atg for chemo-induced vomiting
   b. Benzodiazepines - reduce anxiety-induced vomiting
8. Vomit Inducers:
   a. Ipecacuana
   b. Apomorphine - strong dopamine agonist

Question 2

Physiology of Vomiting

Answer 2

1. Vestibular system - responsible for motion sickness; H1 and M1.
2. Chemoreceptor Trigger Zone - in area postrema (IV ventricle); D2, NK1 and chemoreceptors; fenestrated capillaries allow noxious stimuli through BBB for detection.
3. Vomiting Center - solitary tract nucleus (medulla); H1, NK1 and NK1.
4. GI tract / Heart - mechano-/chemoreceptors and 5HT3.
5. Higher CNS input to the CTZ and VC can induce / inhibit vomiting.

Question 3

H1 Antagonists (MOA, drugs, SE)

Answer 3

MOA:
H1 blockade in vestibular system and vomiting center (solitary nucleus) → for motion sickness
as 1st gen. antihistamines, these drugs cross the BBB; also block M1.

Drugs:

1. Diphenhydramine
2. Dimenhydrinate
3. Promethazine (also inhibits D2 → EPS + ↑ PRL)

Side Effects:

1. drowsiness
2. cognitive dysfunction
3. antimuscarinic effects

Question 4

Muscarinic Antagonists (MOA, drugs)

Answer 4

MOA: 
muscarinic blockade (M1) in the vestibular system → motion sickness only

Drugs:
1. Scopolamine - short DOA → extended-release transdermal patch for motion sickness prophylaxis.

Question 5

D2 Antagonists (MOA, drugs)

Answer 5

MOA:
D2 blockade in the area postrema (CTZ)

Drugs:

1. Chlorpromazine
2. Thiethylperazine
3. Haloperidol - strong D2 atg → only for severe acute nausea (late stage cancer / perioperative).
4. Metoclopramide - also a 5-HT3 atg and 5-HT4 ag (pro-kinetic effect).
   * weak central D2 atg side effects; also available as suppository
   * also useful for post-surgical delayed gastric emptying + diabetic gastroparesis
   * CI in small bowel obstruction
   * may cause diarrhea, drowsiness, depression, EPS, NMS, ↑ PRL and long QT
5. Domperidone - very little BBB crossing → weaker anti-nausea effects, but low EPS risk

Question 6

5-HT3 Antagonists (MOA, drugs, SE)

Answer 6

MOA:
5-HT3 blockade in GI tract → good for chemo-induced or post-op vomiting.

Drugs:

1. Ondansetron
2. Granisetron
3. Palonosetron (parenteral only)
   * “Paleo granny dances on” (despite her nausea… probably because of that healthy low-carb diet).

Side Effects:

1. constipation
2. HA / dizziness
3. long QT
4. serotonin syndrome

Question 7

Neurokinin-1 Receptor Antagonists (MOA, drugs)

Answer 7

MOA:
NK1 blockade in the area postrema (CTZ) and solitary nucleus (VC) → for chemo-induced vomiting
* NK1-R is activated by substance P
* often combined with 5-HT3 atg

Drugs:

1. Aprepitant
2. Fosaprepitant

Question 8

CB1 Agonists = Cannabinoids (MOA, drugs, SE)

Answer 8

MOA:
CB1 agonism → unclear mechanisms leading to ↓ nausea and ↑ appetite.

Drugs:

1. Nabilone - for chemo nausea + neuropathic pain
2. Dronabinol (synthetic THC) - for nausea in chemo + AIDS patients

Side Effects:

1. euphoria
2. hallucinations
3. tachycardia

Question 9

Prokinetic Drugs

Answer 9

1. Neostigmine (ACh-ase inhibitor) and Bethanechol (M-selective agonist)
   Indications:
   Post-op - for ileus; CI in obstructive ileus!
2. Metoclopramide / Domperidone - modulate cholinergic neuron function in GI tract → ↑ motility; 5-HT4 agonism of metoclopramide is prokinetic.
3. Prucalopride - 5-HT4 agonist for ↑ motility.
4. (Cisapride / Tegaserod - withdrawn due to cardiotoxicity; 5-HT4 agonists).
5. (Erythromycin - has motilin-like metabolite which increases motility).