Antiemetics: Nausea & Vomiting Flashcards
List SEVEN major classes of drugs used for the treatment of nausea and vomiting.
(1) Serotonin 5-HT3 antagonists (Ondansetron, Granisetron, Palanosetron)
(2) Corticosteroids (Dexamethaosone, Methylprednisolone)
(3) Neurokinin receptor antagonists (Aprepitant, Fosaprepitant, “pitant)
(4) Dopamine receptor antagonists (Metoclopramide, Promethazine, Olanzapine)
(5) Muscarinic receptor antagonists (Anticholinergics), for motion sickness (Hyoscine)
(6) H1 histamine receptor antihistamines - e.g. Cinnarizine
(7) Benzodiazepines - Lorazepam, “azepam, “zolam
Serotonin, Dopamine, Neurokinin,
Coricosteroids, Anticholinergics, CNS
Name TWO examples of antiemetic serotonin 5-HT3 antagonists
Ondansetron, granisetron, palonosetron, and other *setrons
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.
(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
Briefly describe the mechanism of action of 5-HT3 antagonist antiemetics and describe their use in the treatment of chemotherapy-induced nausea and vomiting.
- 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)
Name an example of a corticosteroid used in the treatment of chemotherapy-induced nausea and vomiting. (CINV)
Dexamethasone, methylprednisolone
Briefly discuss the adverse effects of corticosteroids used as antiemetics for chemotherapy-induced nausea and vomiting.
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
Name an example of a dopamine receptor antagonist used as an antiemetic.
Metoclopramide
Describe the mechanism of action of dopamine receptor antagonists as antiemetics
Dopamine, especially dopamine D2, receptor antagonism in the chemoreceptor trigger zone (CTZ).
Discuss the adverse effects of dopamine receptor antagonists.
- 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
What are the recommended options for the treatment of acute nausea and vomiting induced by a chemotherapy regimen expected to have low emetogenic risk?
A 5-HT3 receptor antagonists OR dexamethasone OR a dopamine receptor antagonist
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)?
5-HT3 receptor antagonist AND dexamethasone
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?
5-HT3 receptor antagonist AND dexamethasone AND neurokinin NK1 receptor antagonist
Name an example of a neurokinin 1 (NK1) receptor antagonist used to treat nausea and vomiting.
Aprepitant, fosaprepitant or any other *pitant
Discuss the routes of administration of aprepitant and fosaprepitant.
Aprepitant is administered oral. Fosaprepitant is an intravenously administered prodrug of aprepitant.
Briefly explain the mechanism of action of neurokinin NK1 receptor antagonists in treating nausea and vomiting.
Neurokinin NK1 receptor antagonists directly antagonize NK1 receptors in the chemoreceptor trigger zone of the area postrema.
List major adverse effects and concerns with the use of neurokinin NK1 receptor antagonists
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
Name THREE examples of mixed dopamine, muscarinic and/or histamine receptor antagonists
- 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
List major concerns with and adverse effects of mixed dopamine, muscarinic and/or histamine receptor antagonist antiemetics.
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
Name ONE example of a benzodiazepine used to manage anticipatory nausea and vomiting.
Lorazepam, diazepam
Briefly explain the use of benzodiazepines in the treatment of nausea and vomiting.
- Binding to an allosteric site on GABAA receptors increases chloride conductance
- Anxiolytic
- Reduce anticipatory vomiting or vomiting caused by anxiety
Discuss the major concerns with and adverse effects of benzodiazepines.
Major concerns / adverse effects:
- 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)
Name TWO drugs commonly used for the treatment of motion sickness induced nausea and vomiting.
Scopolamine (also known as hyoscine), diphenhydramine
Briefly discuss the mechanisms of action and adverse effects of scopolamine.
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
Briefly discuss the mechanisms of action and adverse effects of diphenhydramine when used as an antiemetic.
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
List the 7 major targets for the treatment of nausea and vomiting
(1) Gastrointestinal System signals &
Chemoreceptor trigger zone detects toxins in blood
–> 5-HT3 antagonists
( Serotonin 5-HT3 antagonists)
(2) Systemic Mechanisms –> ( Corticosteroids )
(3) Chemoreceptor trigger zone detects toxins in blood
–> ( Dopamine D2 receptor antagonists )
(4) Chemoreceptor trigger zone detects toxins in blood
–> ( Neurokinin 1 receptor antagonists )
(5) Vestibular system signals –> (Muscarinic Receptor Antagonists)
(6) Vestibular system signals –> (H1 Histamine Receptor Antagonists)
(7) CNS signals: (Benzodiazepines)
Which of the following statements BEST describes ondansetron?
1) Neurokinin NK1 antagonist
2) Corticosteroid
3) 5-HT3 receptor antagonist
4) Muscarinic acetylcholine receptor antagonist
5-HT3 receptor antagonist
Which of the following is MOST important to monitor in patient administered ondansetron?
1) Rigidity
2) Blood dyscrasias
3) Headache
4) Chest pain
Chest pain
Which of the following drugs is a neurokinin NK1 antagonist?
1) Netupitant
2) Palonosetron
3) Prochlorperazine
4) Diphenhydramine
Netupitant
Which of the following is it MOST important to monitor a patient administered metoclopramide for?
1) Constipation
2) Tremor
3) Palpitations
4) Dry mouth
Tremor
Which of the following drug classes is MOST likely to interact with lorazepam?
1) Non-steroidal anti-inflammatory drugs
2) Opioid analgesics
3) Antihypertensive drugs
4) Chemotherapeutic drugs
Opioid
Which of the following classes of drug is MOST appropriate for motion sickness?
1) Mixed dopamine and muscarinic antagonists
2) Muscarinic antagonists and H1 antihistamines
3) 5-HT3 antagonists
4) Corticosteroids
Muscarinic antagonists and H1 antihistamines
Which of the following is MOST likely an adverse effect of hyoscine?
1) Blurred vision
2) Diarrhoea
3) Headache
4) Urinary incontinence
Blurred vision
In addition to treating motion sickness, which of the following is a useful clinical effect of hyoscine?
(1) Antispasmodic
(2) Prokinetic
(3) Anti-inflammatory
(4) Analgesic
Antispasmodic
E-Lecture (E.g. 1.1):
Following left hemicolectomy to surgically remove a colorectal adenocarcinoma, Tan Mei Ling, a 46-year-old woman, was diagnosed with metastatic cancer.
She was prescribed a chemotherapy regimen that is expected to have a LOW risk of being emetic.
What would be the MOST appropriate drug(s) to prevent ACUTE nausea and vomiting?
Refer to flow chart Adapted from MASCC/ESMO Antiemetic Guideline 2016 updated 2020/2023
5-HT3 or DEX or DOP
5-HT3 = serotonin3 receptor antagonist –> Ondansetron
DEX = DEXAMETHASONE (a type of corticosteroids)
DOP = dopamine receptor antagonist (e.g. Metoclopramide)
E-Lecture (E.g. 1.2):
Following left hemicolectomy to surgically remove a colorectal adenocarcinoma, Tan Mei Ling, a 46-year-old woman, was diagnosed with metastatic cancer.
She was switched to a chemotherapy regimen that is expected to have a HIGH risk of being emetic.
What would be the MOST appropriate drug(s) to prevent ACUTE nausea and vomiting?
Refer to flow chart Adapted from MASCC/ESMO Antiemetic Guideline 2016 updated 2020/2023
5-HT3 + DEX + NK1
5-HT3 = serotonin3 receptor antagonist
DEX = DEXAMETHASONE
NK1 = neurokinin1 receptor antagonist such as APREPITANT or FOSAPREPITANT or NEPA (combination of netupitant and palonosetron)
E-Lecture (E.g. 1.3):
Tan Mei Ling was switched to a chemotherapy regimen that is expected to have a HIGH risk of being emetic. She was prescribed palonosetron + dexamethasone + aprepitant before chemotherapy.
She had little nausea and no vomiting on the day of chemotherapy but experienced nausea and vomiting over the next three days.
What would be the MOST appropriate drug(s) to prevent DELAYED nausea and vomiting?
Refer to flow chart Adapted from MASCC/ESMO Antiemetic Guideline 2016 updated 2020/2023
We can have 1 day regimen or 4 day regimen ???
E-Lecture (E.g. 1.4):
Tan Mei Ling experienced severe nausea and vomiting while on a highly emetogenic chemotherapy regimen.
The next time she came to the clinic for chemotherapy she was visibly anxious and experienced severe nausea and vomiting even BEFORE having her chemotherapy administered.
What would be the MOST appropriate drug(s) to prevent ANTICIPATORY nausea and vomiting?
Benzodiazepines
Examples:– Lorazepam, diazepam
Mechanisms:
- Binding to allosteric site on GABAAreceptors increases chloride conductance
– Anxiolytic
– Reduce anticipatory vomiting or vomiting caused by anxiety
Major concerns / adverse effects:
– 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)
E-Lecture (2):
A 22-year-old man suffers from severe motion sickness.
Which drug(s) would be MOST appropriate for preventing motion sickness?
Muscarinic Receptor Antagonists : Anticholinergic Drugs
Examples: – Hyoscine
Also used as an antispasmodic for abdominal cramps as anticholinergic muscarinic receptor antagonism reduces gastrointestinal motility and secretions.
