Anti-emetics

Question 1

Cause of nausea and vomiting (1)

Answer 1

Chemotherapy (cisplatin) induced nausea & vomiting (CINV)

Question 2

Explain the pathophysiology behind cisplatin induced nausea and vomiting

Answer 2

Cisplatin is toxic to enterochromaffin cells in the stomach => release of free radicals => excessive 5-HT release

5-HT activates 5-HT3A receptors on nerve fibres to chemoreceptor trigger zone (CTZ)
CTZ activates nerves fibres to vomiting centre (VC) via muscarinic receptors
VC => nausea

Question 3

List the drugs used in the treatment of CINV and explain their use.

Answer 3

TRIPLE THERAPY

1. Ondansetron = 5-HT3A receptor antagonist
2. Glucocorticoids = reduce free radical production
3. Aprepitant = neurokinin-1 receptor* antagonist

Neurokinin-1 receptors primary expressed in the VC and are activated by substance-P

Question 4

Why is triple therapy used for CINV?

Answer 4

Chemotherapy induces nausea and vomiting very acutely and then again much later (bi-phasic nausea and vomiting induction)

Ondansetron is good for the first phase
Glucocorticoids + Aprepitant are good for the later second phase

Question 5

Cause of nausea and vomiting (2)

Answer 5

Motion sickness

Question 6

Explain the pathophysiology behind motion sickness

Answer 6

Labyrinth - neural mismatch => activates histamine receptors on vestibular nuclei

Vestibular nuclei activate muscarinic receptors on CTZ

CTZ activates VC, which causes nausea

Question 7

List the two drugs commonly used in the treatment of motion sickness and explain their use

Answer 7

Promethazine = H1 receptor antagonist

Hyoscine (scopolomine) = non-selective muscarinic receptor antagonist

Question 8

Cause of nausea and vomiting (3)

Answer 8

Gastroparesis = delayed emptying of the stomach

due to reduced stomach contraction

Question 9

Explain why gastroparesis can cause nausea and vomiting

Answer 9

=> increased 5-HT release which activates 5-HT3A receptors on CTZ
CTZ activates nerves fibres to vomiting centre (VC)
VC => nausea

Question 10

Which drug is used in the treatment of nausea and vomiting caused by gastroparesis? Describe its two actions

Answer 10

Metoclopramide

1. *Dopamine D2 receptor antagonist
   => stimulates gastric emptying (prokinetic)
   => Inhibits D2 receptors in CTZ
2. 5-HT3A receptor antagonist
   => Inhibits activation of CTZ

Dopamine receptors are expressed in the CTZ

Question 11

Summarise the mechanistic triggers of nausea and vomiting

Answer 11

Cytotoxic drugs, motion sickness, gastrointestinal problems, pregnancy, other higher functions

Question 12

Identify the main classes of anti-emetic drugs and outline their principle clinical uses

Answer 12

5-HT3A receptor antagonists: chemotherapy induced N&V

Histamine H1 receptor antagonists: motion sickness

Muscarinic receptor antagonists: motion sickness

Dopamine D2 receptor antagonists: gastroparesis induced N&V

Question 13

What side-effects would you expect from centrally acting muscarinic receptor antagonists?

Answer 13

Drowsiness

Dry mouth

Question 14

What side-effect would you associate with histamine H1 receptor antagonism?

Answer 14

Drowsiness

Question 15

What side-effects would you associate with dopamine D2 receptor antagonism?

Answer 15

Galactorrhoea

Extrapyramidal side-effects

Question 16

What side-effects would you associate with 5HT3A receptor antagonism?

Answer 16

Constipation

Headaches