24. Antiemetics

Question 1

why does chemotherapy induce nausea and vomiting?

Answer 1

chemotherapy agents (e.g. cisplatin) are toxic to the stomach

1. cisplatin affects enterochromaffin cells and causes their destruction
2. this leads to free radicals being released –> excessive 5-HT release from the stomach
3. serotonin acts on 5-HT3a receptors located on nerve fibres to i) the nucleus tractus solitarius (–> nerves to the vomiting centre), ii) nerve fibres to the vomiting centre and iii) nerve fibres to chemoreceptor trigger zone

Question 2

how is chemotherapy induced nausea and vomiting (CINV) treated?

Answer 2

blocking the 5-HT receptors e.g. administering Ondansteron - 5-HT3a receptor antagonist

should be given with glucocorticoids (to reduce free radical production) and aprepitant (neurokinin-1 receptor antagonist)

Question 3

what is the relevance of neurokinin-1 receptors?

Answer 3

located in the connection between the solitary tract and the vomiting centre

substance P acts on these NK-1 receptors

inhibiting these receptors will inhibit vomiting

Question 4

why can motion cause sickness?

Answer 4

there is a neural mismatch between the labyrinth and CNS

• a signal from the labyrinth is mediated through muscarinic receptors
• the signal is received by the hypothalamus
• the hypothalamus can communicate with the chemoreceptor trigger zone via histamines acting on H1 receptor
• the signal says there is a mismatch –> activation of the chemoreceptor trigger zone –> nausea and vomiting

Question 5

what is the relevance of the vestibular system?

Answer 5

communicates with the hypothalamus (indirect connection to the CTZ) as well as directly with the vomiting centre (M1-5 receptors)

connections are mediated through muscarinic receptors, histamine receptors and dopamine receptors

Question 6

what can be used to treat motion sickness?

Answer 6

• promethazine

- hyoscine

Question 7

describe the use of Promethazine in treating motion sickness

Answer 7

• H1 receptor antagonist
• blocks the H1 receptor (pre-synaptic or post-synaptic) which is involved in the signalling process from the hypothalamus to the CTZ
• blockade reduces the likeliness of vomiting being triggered

Question 8

describe the use of Hyoscine in treating motion sickness

Answer 8

• non-selective muscarinic antagonist
• most effective
• blocks all 5 of the muscarinic receptors
• prevents signalling from the labyrinth –> vestibular system and from the vestibular system –> vomiting centre

Question 9

what are people with a history of T2DM likely to suffer from?

Answer 9

gastroparesis: delayed emptying of the stomach (it cannot contract properly) so food remains in the stomach which triggers the vomiting reflex

Question 10

describe the pathophysiology of gastroperesis

Answer 10

delayed stomach emptying –> reduced stomach contraction –> 5-HT release –> activation of 5-HT receptors on nerve fibres to vomiting centre and CTZ

Question 11

what is the first line treatment for gastroperesis? why?

Answer 11

dopamine D2 receptor antagonist

more effective than 5-HT receptor antagonists

Question 12

name and describe the actions of a dopamine D2 receptor antagonist

Answer 12

METOCLOPRAMIDE

• stimulates gastric emptying by acting on the stomach itself (stimulates contractility)
• inhibits D2 receptors in the vomiting centre
• is also a 5-HT3a receptor antagonist –> inhibits activation of CTZ

Question 13

summarise the physiological control of nausea/vomiting

Answer 13

• vomiting centre innervated by the nucleus of the tractus solitarius
• chemoreceptor trigger zone - communicates with the vomiting centre

Question 14

what are the main mechanistic triggers for nausea/vomiting?

Answer 14

• cytotoxic drugs
• motion sickness
• GI problems

Question 15

outline the main classes of anti-emetic drugs

Answer 15

• 5-HT3a receptor antagonists
• histamine H1 receptor antagonists
• muscarinic receptor antagonists
• dopamine D2 receptor antagonists

Question 16

outline the principle clinical uses and mechanisms of action of the anti-emetic drugs

Answer 16

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 17

outline the principle side effects of each class of anti-emetic drug

Answer 17

5-HT3a receptor antagonists: headaches and constipation

histamine H1 receptor antagonists: drowsiness

muscarinic receptor antagonists: constipation, drowsiness and dry mouth

dopamine D2 receptor antagonists: extra-pyramidal side effects