Anti-emetics (10.03.2020) Flashcards
CINV
Chemotherapy induced nausea & vomiting (CINV)
- e.g. cisplatin
Treatment of CINV
Triple Therapy:
- Ondansetron - 5-HT3A receptor antagonist (used for early stage N&V)
- Glucocorticoids - reduce free radical production (used for late stage N&V)
- Aprepitant - neurokinin-1 receptor antagonist (used for late stage N&V)
Ondansetron
= 5-HT3A receptor antagonist
- 5-HT3A receptors are found on nerve fibres going to CTZ
- dansetron = 5HT receptor antagonist
Promethazine
- Promethazine - H1 receptor antagonist (expressed vestibular nuclei which are activated due to neural mismatch in motion sickness)
- used in motion sickness
- OTC
Hyoscine (scopolomine)
– non-selective muscarinic receptor antagonist
- centrally acting non-selective muscarinic receptor antagonist
- acts on CTZ and VC -> not only used for motion sickness but also in end-of-life care.
- SE: constipation, dizziness, drowsiness, dry mouth, dyspepsia…
Metoclopramide
Dual action
- Dopamine D2 receptor antagonist
- Prokinetic – stimulates gastric emptying
- Inhibits D2 receptors in CTZ
- 5-HT3A receptor antagonist
- Inhibits activation of CTZ
would be also good to treat drug induced N&V?
Pathophysiology of CINV
- chemotherapy agent (e.g. cisplatin) is toxic to cells and causes release fo free radicals leading to excessive 5HT release
- 5HT activates 5HT3A receptors on nerve fibres to chemoreceptor trigger zone (CTZ)
- CTZ activates nerve fibres going to the vomiting center (muscarinic receptors 1-5 at VC)
- activation of the VC causes N&V
What is vomiting
the forceful oral expulsion of gastric contents.
Neurokinin 1 receptor antagonists in CINV treatment
- neurokinin 1 R is found in area posterma of the VC
- activated by substance P (which is related from higher centres of the brain and is involved in pain perception)
- used for late N&V in CINV
- e.g. aprepitant
Biphasic response fo N&V
in CIMV
early N&V -> Ondansetron (5HT3A R antagonist)
late N&V -> GC and neurokinin-1 R antagonist
Pathophysiology of motion sickness
- Labyrinth - neural mismatch between what you see and what you feel -> activates histamine1 receptors on vestibular nuclei
- Vestibular nuclei activate muscarinic (M1-5) receptors on CTZ
- CTZ activates VC, which causes nausea
Where are the muscarinic receptors in the pathway that causes nausea?
- on the VC
- also on CTZ
- activation of the M1-5 muscarinic receptors -> N&V
Treatment of motion sickness
- Promethazine - H1 receptor antagonist
- Hyoscine (scopolomine) – non-selective muscarinic receptor antagonist
Gastroparesis
- delayed emptying of the stomach
- reduced stomach contraction
Pathophysiology of gastroparesis
- 5-HT – activates 5-HT3A receptors on CTZ
- CTZ activates nerves fibres to vomiting centre (VC)
- VC -> nausea
Where is the pathogenesis leading to N&V not well understood?
- in pregnancy
- as a reaction to seeing or hearing something repulseive
Physiological control of N&V
- Chemoreceptor Trigger Zone (CTZ): receives multiple inputs from areas including stomach & vestibular nuclei
- CTZ: communicates with the vomiting centre -> nausea & vomiting
Mechanistic triggers to N&V
Cytotoxic drugs, motion sickness, gastrointestinal problems, pregnancy, other higher functions
What are the main classes of anti-emetic drugs?
- 5-HT3A receptor antagonists (e.g. Ondansetron)
- Histamine H1 receptor antagonists (e.g. Promethazine)
- Muscarinic receptor antagonists (e.g. hyoscine = scopolomine)
- Dopamine D2 receptor antagonists (e.g. Metoclopramide but this also acts as a 5HT3A R antagonist)
When are the different classes of anti-emetic drugs used?
- 5-HT3A receptor antagonists: chemotherapy induced N&V (e.g. Ondansetron)
- Histamine H1 receptor antagonists: motion sickness
- Muscarinic receptor antagonists: motion sickness (e.g. hyoscine = scopolomine)
- Dopamine D2 receptor antagonists: gastroparesis induced N&V
What are the SEs of the different anti-emetics?
- 5-HT3A receptor antagonists: Headaches, constipation
- Histamine H1 receptor antagonists: drowsiness
- Muscarinic receptor antagonists: dry mouth, drowsiness
- Dopamine D2 receptor antagonists: galactorrhoea, extrapyramidal SE
Treatment of gastroparesis induced N&V
Metoclopramide:
- Dopamine D2 receptor antagonist &
- 5-HT3A receptor antagonist
