Nausea & Vomiting

Question 1

List SEVEN major classes of drugs used for the treatment of nausea and vomiting.

Answer 1

(1) Serotonin 5-HT3 antagonists
(2) Corticosteroids
(3) Neurokinin receptor antagonists
(4) Dopamine receptor antagonists
(5) Muscarinic receptor antagonists
(6) H1 histamine receptor antihistamines
(7) Benzodiazepines

Question 2

Name TWO examples of antiemetic serotonin 5-HT3 antagonists

Answer 2

Ondansetron, granisetron, palonosetron, and other *setrons

Question 3

Name an example of (1) a first-generation and (2) a second-generation 5-HT3 antagonist anti-emetic. State the half-life of these drugs.

Answer 3

(1) First-generation:
- Ondansetron (half-life 4-9 hrs)
(2) Second-generation:
- Granisetron: half-life 9-12 hrs in cancer patients
- Palonosetron: half-life 40-50 hrs

Question 4

Briefly describe the mechanism of action of 5-HT3 antagonist antiemetics and describe their use in the treatment of chemotherapy-induced nausea and vomiting.

Answer 4

• Act at 5-HT3receptors primarily in the GIT
• CNS 5-HT3receptors do not appear to play an important role in actions in nausea and vomiting
• Efficacy enhanced by combination with a corticosteroid and NK1-receptor antagonist
• Intravenously 30 min before or orally 1 hour before chemotherapy to prevention of acute chemotherapy-induced nausea and vomiting (CINV).
• Generally not effective for delayed nausea and vomiting (>24 hr after chemotherapy)

Question 5

Name an example of a corticosteroid used in the treatment of chemotherapy-induced nausea and vomiting.

Answer 5

Dexamethasone, methylprednisolone

Question 6

Briefly discuss the adverse effects of corticosteroids used as antiemetics for chemotherapy-induced nausea and vomiting.

Answer 6

Major concerns / adverse effects:
: Unlikely to occur with short-term use
: Higher doses or longer-term use (> 2 weeks) may cause iatrogenic Cushing’s syndrome, including:
- Redistribution of fat (rounded face)
- Muscle wasting
- Thinning of skin, easy bruising
- Hyperglycaemia, later diabetes
- Osteoporosis
- Immunosuppression

Question 7

Name an example of a dopamine receptor antagonist used as an antiemetic.

Answer 7

Metoclopramide

Question 8

Describe the mechanism of action of dopamine receptor antagonists as antiemetics

Answer 8

Dopamine, especially dopamine D2, receptor antagonism in the chemoreceptor trigger zone (CTZ).

Question 9

Discuss the adverse effects of dopamine receptor antagonists.

Answer 9

Major concerns / adverse effects:
Extrapyramidal side effects:
- Restlessness, dystonia, and parkinsonian symptoms
- The elderly are especially susceptible
- On long-term treatment, irreversible tardive dyskinesia can develop
=> Therefore, only used short-term

Elevated prolactin levels can cause:
Galactorrhoea, gynaecomastia, impotence and menstrual disorders

Question 10

What are the recommended options for the treatment of acute nausea and vomiting induced by a chemotherapy regimen expected to have low emetogenic risk?

Answer 10

A 5-HT3 receptor antagonists OR dexamethasone OR a dopamine receptor antagonist

Question 11

What are the recommended options for the treatment of acute nausea and vomiting induced by a chemotherapy regimen expected to have moderate emetogenic risk (other than carboplatin)?

Answer 11

5-HT3 receptor antagonist AND dexamethasone

Question 12

What are the recommended options for the treatment of acute nausea and vomiting induced by a chemotherapy regimen expected to have a high emetogenic risk or carboplatin?

Answer 12

5-HT3 receptor antagonist AND dexamethasone AND neurokinin NK1 receptor antagonist

Question 13

Name an example of a neurokinin 1 (NK1) receptor antagonist used to treat nausea and vomiting.

Answer 13

Aprepitant, fosaprepitant or any other *pitant

Question 14

Discuss the routes of administration of aprepitant and fosaprepitant.

Answer 14

Aprepitant is administered oral. Fosaprepitant is an intravenously administered prodrug of aprepitant.

Question 15

Briefly explain the mechanism of action of neurokinin NK1 receptor antagonists in treating nausea and vomiting.

Answer 15

Neurokinin NK1 receptor antagonists directly antagonize NK1 receptors in the chemoreceptor trigger zone of the area postrema.

Question 16

List major adverse effects and concerns with the use of neurokinin NK1 receptor antagonists

Answer 16

Major concerns / adverse effects:
: Fatigue, dizziness, diarrhoea
: Metabolism by CYP3A4
- Interaction with various chemotherapeutic agents (e.g., docetaxel, etoposide, irinotecan, imatinib, vinblastine)
- Drugs that inhibit CYP3A4 may influence plasma levels e.g., ketoconazole, clarithromycin, ritonavir, verapamil

Question 17

Name THREE examples of mixed dopamine, muscarinic and/or histamine receptor antagonists

Answer 17

Phenothiazines: prochlorperazine, promethazine
- Dopamine, muscarinic & histamine receptor antagonism

Butyrophenones: droperidol
- Dopamine receptor antagonism and weak histamine receptor antagonism

Atypical antipsychotic: olanzapine
- Dopamine, muscarinic & histamine receptor antagonism
- Also 5-HT3 receptor antagonism

Question 18

List major concerns with and adverse effects of mixed dopamine, muscarinic and/or histamine receptor antagonist antiemetics.

Answer 18

Main concerns / adverse effects:
- Sedative (due to antihistamine effects)
- Extrapyramidal side-effects [EPS] (e.g. Parkinsonian motor adverse effects)
=> Olanzapine: Controls CINV delayed nausea with less EPS
- Hypotension
- Droperidol: prolongation of the QT interval

Question 19

Name ONE example of a benzodiazepine used to manage anticipatory nausea and vomiting.

Answer 19

Lorazepam, diazepam

Question 20

Briefly explain the use of benzodiazepines in the treatment of nausea and vomiting.

Answer 20

• Binding to an allosteric site on GABAA receptors increases chloride conductance
• Anxiolytic
• Reduce anticipatory vomiting or vomiting caused by anxiety

Question 21

Discuss the major concerns with and adverse effects of benzodiazepines.

Answer 21

Sedative / hypnotic

Additive effects with other sedative drugs and CNS depressants e.g., antidepressants, alcohol and opioids
- Respiratory depression on overdose

Avoid during pregnancy, especially first trimester (risk of cleft palate)

Question 22

Name TWO drugs commonly used for the treatment of motion sickness induced nausea and vomiting.

Answer 22

Scopolamine (also known as hyoscine), diphenhydramine

Question 23

Briefly discuss the mechanisms of action and adverse effects of scopolamine.

Answer 23

Mechanisms:
- Muscarinic receptor antagonist (action in vestibular system and vomiting centre)
- Used for prevention of motion sickness

Major concerns / adverse effects:
- Anticholinergic(parasympatholytic) adverse effects:
- Dry mouth, blurring of vision, constipation
- High incidence of adverse effects when given orally therefore often administered by transdermal patch

Question 24

Briefly discuss the mechanisms of action and adverse effects of diphenhydramine when used as an antiemetic.

Answer 24

Mechanisms:
- H1 histamine receptor antagonism (vomiting center and ?vestibular system)
- M1 cholinergic receptor antagonism (vomiting centre and vestibular system)
- Particularly useful for the treatment of motion sickness
- Sedative effects of diphenhydramine may also be useful in treatment of emesis due to chemotherapy

Major concerns / adverse effects:
- Sedative due to antagonism of H1 receptors
- Anticholinergic (parasympatholytic) adverse effects:
- Dry mouth, blurring of vision, constipation