This document discusses various antiemetic agents used to treat nausea and vomiting. It begins by outlining common causes of nausea and vomiting and the pathophysiology involving the vomiting center and chemoreceptor trigger zone in the brainstem. It then summarizes the mechanisms and clinical uses of major classes of antiemetics including 5-HT3 receptor antagonists, corticosteroids, neurokinin 1 receptor antagonists, phenothiazines, substituted benzamides, anticholinergics, antihistamines, benzodiazepines, and cannabinoids. Adverse effects and drug interactions are also briefly mentioned for each class.

1. Antiemetic agents
Domina
Petric, MD

2. Introduction
Causes of nausea and vomiting:
• adverse effects from medicinations
• systemic disorders or infections
• pregnancy
• vestibular dysfunction
• central nervous system infection or increased
intracranial pressure
• peritonitis
• hepatobiliary disorders
• radiation or chemotherapy
• gastrointestinal obstruction
• dysmotility, infections

3. Pathophysiology
• The brainstem ˝vomiting center˝ is loosely
organized neuronal region within the lateral
medullary reticular formation.
• It coordinates the complex act of vomiting
through interactions with cranial nerves VIII
and X, and neural networks in the nucleus
tractus solitarius, that control respiratory,
salivatory and vasomotor centers.
• High concentrations of muscarinic M1,
histamine H1, neurokinin 1 (NK1) and serotonin
5-HT3 receptors are present in the vomiting
center.

4. Pathophysiology
Important sources of afferent input to
the vomiting center are:
• chemoreceptor trigger zone
• vestibular system
• vagal and spinal afferent nerves
from the GI tract
• central nervous system

5. Chemoreceptor trigger zone
• It is also called area postrema.
• It is located at the caudal end of
the fourth ventricle.
• It is outside the blood-brain
barrier, but accessible to
emetogenic stimuli in the blood
and cerebrospinal fluid.

6. Source: Pinterest.com

7. Chemoreceptor trigger zone
It is rich in dopamine D2
receptors and opioid
receptors, and possibly
serotonin 5-HT3 receptors
and NK1 receptors.

8. The vestibular system
It is important in motion
sikness via cranial nerve VIII.
It is rich in muscarinic M1 and
histamine H1 receptors.

9. Image source: Vimeo.com

10. Vagal and spinal nerves
Vagal ans spinal afferent
nerves from the
gastrointestinal tract are
rich in 5-HT3 receptors.
Irritation of the GI mucosa by
chemotherapy, radiation
therapy, distention or acute
infectious gastroenteritis leads to
release of mucosal serotonin.

11. Vagal and spinal nerves
• Mucosal serotonin activates
serotonin receptors.
• Activation of receptors
stimulates vagal afferent input
to the vomiting center and
chemoreceptor trigger zone.

12. CNS
The central nervous
system plays a role in
vomiting due to psychiatric
disorders, stress and
anticipatory vomiting prior
to cancer chemotherapy.

13. SEROTONIN 5-HT3
ANTAGONISTS

14. Pharmacology
Selective
5-HT3 receptor
antagonists
have potent
antiemetic
properties that
are mediated
through:
• central 5-HT3
receptors
blockade in the
vomiting center
• chemoreceptor
trigger zone
• blockade of
peripheral 5-HT3
receptors on
extrinsic
intestinal vagal
and spinal
afferent nerves
PARTIALLYMAINLY

15. Pharmacology
• The antiemetic action of these
agents is restricted to emesis
atributable to vagal stimulation
(postoperative) and
chemotherapy.
• Other emetic stimuli (motion
sikness) are poorly controlled.

16. Pharmacology
• Ondansetron, granisetron and
dolasetron have a serum half-life of
4-9 hours so they may be
administered once daily by oral or
intravenous routes.
• Palonosetron (iv. agent) has greater
affinity for the 5-HT3 receptor and a
long serum half-life of 40 hours.

17. Pharmacology
• All 4 drugs undergo extensive
hepatic metabolism and are
eliminated by renal and hepatic
excretion.
• Dose reduction is not required in
geriatric patients or patients with
renal insufficiency.

18. Pharmacology

19. Clinical uses
Indications are:
• chemotherapy-induced
nausea and vomiting
• postoperative and
postradiation nausea and
vomiting

20. Chemotherapy
• 5-HT3 receptor antagonists are the
primary agents for the prevention of
acute chemotherapy-induced nausea
and vomiting.
• The drugs are most effective when
given as a single dose by intravenous
injection 30 minutes prior to
administration of chemotherapy.

21. Chemotherapy
Iv. doses are:
• ondansetron 8 mg
• granisetron 1 mg
• dolasetron 100 mg
• palonosetron 0,25 mg

22. Chemotherapy
Oral doses (1 hour before
chemotherapy):
• ondansetron 8 mg twice daily
or 24 mg once daily
• granisetron 2 mg
• dolasetron 100 mg

23. Chemotherapy
Efficacy is enhanced by
combination therapy
with a corticosteroid
(dexamethasone) and
NK1 receptor antagonist.

24. Postoperative, postradiation
• These agents are used to prevent
and treat postoperative nausea and
vomiting.
• They are also effective in the
prevention and treatment of nausea
and vomiting in patients undergoing
radiation therapy to the whole body
or abdomen.

25. Adverse effects
• Well-tolerated agents with excelent
safety profiles.
• Most commonly reported are
headache, dizziness and
constipation.
• Prolongation of the QT interval: all
four agents, most pronounced with
dolasetron.

26. Adverse effects
Dolasetron should not be
administered to patients
with prolonged QT interval
or in conjunction with other
medicinations that may
prolong the QT interval.

27. Drug interactions
• There are no significant drug
interactions.
• All four agents undergo some
metabolism by hepatic cytochrome
P450 system.
• Other drugs may reduce hepatic
clearance of the 5-HT3 receptor
antagonists, altering their half-life.

28. CORTICOSTEROIDS

29. Corticosteroids
Corticosteroids
(dexamethasone,
methylprednisolone) have
antiemetic properties.
These agents enhance the efficacy of
5-HT3 receptor antagonists for
prevention of acute and delayed
nausea and vomiting in patients
receiving moderately to highly
emetogenic chemotherapy regimens.

30. Corticosteroids
Dexamethasone 8-20 mg
iv. before chemotherapy,
followed by 8 mg/d orally
for 2-4 days, is
commonly administered.

31. NEUROKININ RECEPTOR
ANTAGONISTS (NK1-
RECEPTOR ANTAGONISTS)

32. NK1-receptor antagonists
• Neurokinin 1 receptor antagonists
have antiemetic properties that are
mediated through central blockade in
the area postrema.
• Aprepitant is an oral formulation,
highly selective and crosses the
blood-brain barrier.

33. NK1-receptor antagonists
• Aprepitant occupies brain NK1-
receptors.
• It has no affinity for setononin,
dopamine or corticosteroid receptors.
• Fosaprepitant is an iv. formulation.
• It is converted within 30 minutes after
infusion to aprepitant.

34. Pharmacokinetics
The oral bioavailability of
aprepitant is 65%.
The serum half-life is 12 hours.
Aprepitant is metabolized by the liver,
primarily by the CYP3A4 pathway.

35. Clinical use
• Aprepitant is used in combination
with 5-HT3 receptor antagonists
and corticosteroids for the
prevention of acute and delayed
nausea and vomiting from highly
emetogenic chemotherapeutic
regimens.

36. Clinical use
3-days dose regime:
• oral aprepitant 125 mg or iv.
fosaprepitant 115 mg, given 1
hour before chemotherapy
• followed by oral aprepitant in the
dose of 80 mg/d for 2 days after
chemotherapy

37. Adverse effects
Aprepitant may be
associated with
fatigue, dizziness
and diarrhea.

38. Drug interactions
Aprepitant is metabolized by CYP3A4
and may inhibit the metabolism of other
drugs metabolized by the same
enzyme:
• docetaxel, paclitaxel, etoposide
• irinotecan, imatinib, vinblastine
• vincristine

39. Drug interactions
Drugs that inhibit CYP3A4 metabolism
may significantly increase aprepitant
plasma levels:
• ketoconazole, ciprofloxacin
• clarithromycin, nefazodone
• ritonavir, nelfinavir
• verapamil, quinidine

40. Drug interactions
Aprepitant decreases
the international
normalized ratio (INR)
in patients taking
warfarin.

41. PHENOTHIAZINES,
BUTYROPHENONES

42. Phenothiazines
• Antipsychotics that can be used
for their potent antiemetic and
sedative properties.
• The antiemetic properties of
phenothiazines are mediated
through inhibition of dopamine
and muscarinic receptors.

43. Phenothiazines
• Sedative properties are due to
their antihistamine activity.
• The agents most commonly used
as antiemetics are
prochlorperazine, promethazine
and thiethylperazine.

44. Butyrophenones
• Antipsychotics that have antiemetic
properties due to their central
dopaminergic blockade.
• Droperidol can be given by
intramuscular or intravenous
injection.
• In antiemetic doses, droperidol is
extremely sedating.

45. Butyrophenones
• It is not used as much as in the past.
• Droperidol may prolong the QT
interval, rarely resulting in fatal
episodes of ventricular tachycardia
(torsades de pointes).
• It should not be used in patients with
QT prolongation.

46. SUBSTITUTED BENZAMIDES

47. Substituted benzamides
• Those are metoclopramide and
trimethobenzamide.
• Their primary mechanism of
antiemetic action is dopamine-
receptor blockade.
• Trimethobenzamide has also weak
antihistaminic activity.

48. Substituted benzamides
• Metoclopramide is used for
prevention and treatment of nausea
and vomiting 10-20 mg orally or iv.
every 6 hours.
• The usual dose of
trimethobenzamide is 300 mg orally
or 200 mg im. injection.

49. Substituted benzamides
The principal adverse
effects are extrapyramidal:
restlesness, dystonias and
parkinsonian symptoms.

50. ANTICHOLINERGICS,
ANTIHISTAMINES

51. Anticholinergics
• As single agents, these drugs have
weak antiemetic activity.
• Despite that, they are particularly
useful for the prevention or treatment
of motion sickness.
• Adverse effects: dizziness, sedation,
confusion, dry mouth, cycloplegia,
urinary retention.

52. H1 antihistamines
Diphenhydramine and its salt,
dimenhydrinate, are first generation
histamine H1 antagonists that have
significant anticholinergic properties.
Diphenhydramine has sedating properties
and it is commonly used together with
other antiemetics for treatment of emesis
due to chemotherapy.

53. H1 antihistamines
• Meclizine has minimal
anticholinergic properties and
causes less sedation.
• It is used for the prevention of
motion sickness and the
treatment of vertigo due to
labyrinth dysfunction.

54. H1 antihistamines
• Hyoscine (scopolamine) is a
prototypic muscarinic receptor
antagonist.
• It is one of the best agents for the
prevention of motion sickness.
• It has a very high incidence of
anticholinergic effects when given
orally or parenterally.

55. H1 antihistamines
Hyoscine is better
tolerated as a
transdermal
patch.

56. BENZODIAZEPINES

57. Benzodiazepines
Lorazepam and diazepam
are used before the initiation
of chemotherapy to reduce
anticipatory vomiting or
vomiting caused by anxiety.

58. CANNABINOIDS

59. Cannabinoids
• Dronabinol is ∆9-tetrahydrocannabinol
(THC), the major psychoactive
chemical in marijuana.
• After oral ingestion, the drug is
almost completely absorbed, but
undergoes significant first-pass
hepatic metabolism.

60. Cannabinoids
• Metabolites of dronabinol are
excreted slowly over days to
weeks in the feces and urine.
• Dronabinol is used medically
as an appetite stimulant and
as an antiemetic.

61. Cannabinoids
• Combination therapy of dronabinol
and phenothiazines provides
synergistic antiemetic action and
appears to attenuate the adverse
effects of both agents.
• Dosage is 5 mg/m2 just prior to
chemotherapy and every 2-4 hours
as needed.

62. Cannabinoids
• Adverse effects: euphoria, dysphoria,
sedation, hallucinations, dry mouth
and increased appetite.
• It has some autonomic effects that
may result in tachycardia,
conjunctival injection and orthostatic
hypotension.

63. Cannabinoids
• Dronabinol has no significant
drug-drug interactions, but may
potentiate the clinical effects of
other psychoactive agents.
• Nabilone is a closely related
THC analog.

64. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
• Pinterest.com
• Vimeo.com