Antiemetics

Question 1

What are anti-emetics?

Answer 1

Drugs effective against nausea and vomiting

Question 2

Describe the pathophysiology of CINV?

Answer 2

CINV - Chemotherapy induced nausea and vomiting

1) Chemotherapy is toxic to enterochromaffin cells (gastric glands) - resulting in the release of free radicals.
2) Free radicals –> excessive 5-HT release
3) 5-HT activated 5HT3A receptors on:
- Nerve fibres to the NTS
- Nerve fibres to the VC
- Nerve fibres to the CTZ
4) Nausea vomiting

NTS - Nucleus tractus solaris. Projects from the stomach to the medulla oblongata. The NTS projects to the VC.
VC - Vomiting centre in the medulla oblongata. Has motor fibres that go down to the stomach to cause contraction and vomiting.
CTZ - Chemoreceptor trigger zone, outside the BBB = circumventricular organ.

Question 3

How would you treat CINV?

Answer 3

IMPORTANT –> Ondansteron - selective 5-HT3A receptor antagonist

(Glucocorticoids - reduce free radical production
Arepepritant – neurokinin-1 receptor antagonist)

Question 4

Describe the pathophysiology of motion sickness?

Answer 4

1) Auditory labyrinth - neural mismatch - activates the vestibular system (via muscarinic (M) receptors)
2) This causes increased hypothalamic histamine (H) release - activates H1 receptors in CTZ
3) Vestibular system and hypothalamus may also activate the VC though cholinergic system (muscarinic receptors)

Question 5

How do you treat motion sickness?

Answer 5

Promethazine - H1 receptor antagonist

Hyoscine (scopolomine) – non-selective muscarinic receptor antagonist. Blocks muscarinic receptors from labyrinth to vestibular system AND vestibular system to VC.

Question 6

Describe the pathophysiology of gastroparesis?

Answer 6

Delayed emptying of the stomach

1) Reduced stomach contraction
2) 5-HT – activates 5-HT3A receptors on:
- Nerves fibres to VC
- Nerve fibres to CTZ
3) D2 receptors at the VC in the medulla oblongata.

See diagram on slide 8

Question 7

What is the treatment for N and V?

Answer 7

Metoclopramide:

• Dopamine D2 receptor antagonist
  1) Prokinetic – stimulates gastric emptying
  2) Inhibits D2 receptors in VC - reduces nausea and vomiting.
• 5-HT3A receptor antagonist
  1) Inhibits activation of CTZ

Question 8

What are the four classes of anti-emetic drugs?

Answer 8

5-HT3A receptor antagonists

Histamine H1 receptor antagonists

Muscarinic receptor antagonists

Dopamine D2 receptor antagonists

Question 9

Summarise the physiological control of nausea/vomiting and identify the main mechanistic triggers

Answer 9

Physiological control:

• Vomiting centre (area postrema): innervated by the nucleus of the tractus solitarius
• Chemoreceptor Trigger: Zone: communicates with the vomiting centre

Mechanistic triggers
Cytotoxic drugs, motion sickness, gastrointestinal problems

Question 10

Summarise the side effect profile of each class of anti-emetic drug?

Answer 10

5-HT3A receptor antagonists: constipation and headaches

Histamine H1 receptor antagonists: drowsiness

Muscarinic receptor antagonists: drowsiness, dry mouth

Dopamine D2 receptor antagonists: galactorrea and extra-pyramidal side effects