postrema in the floor of the fourth ventricle, the nucleus
tractus solitarius in the medulla, and various motor nuclei
Antiemetic Medications
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Indications
Nausea is a commonly encountered symptom in healthcare,
one that is difficult for any patient. Causes may be as simple
as the body's defense against an ingested toxin, to a complex
association set of signals activated my motion, medications,
anesthesia, position, stress, pregnancy, psychiatric
disorder, and/or fear. Multiple or single neurohumoral
pathways may be involved. Indications for treatment of
symptoms requires astute evaluation by the treating
provider. Therapy to treat chronic nausea stemming from
chemotherapeutic agents and doses will vary from the
treatment of postoperative nausea (a relatively common side
effect of general anesthesia) and vomiting.[1] Acute onset
nausea/emesis is more likely related to a defined insult or
problem and may require a minimal or short duration of
treatment. Chronic nausea is more likely to be multi-factorial,
require longer therapy, and may be more difficult to treat. No
rule of thumb can be applied when treating nausea. Empiric
treatment of nausea in the absence of a clear diagnosis is
typically well tolerated and may result in a significant benefit
to the patient. Practitioners should be wary of overlooking
surgical emergencies such as small bowel obstructions,
perforated viscus, and acute appendicitis, among others.
Pregnancy should be considered in women of child-bearing
age.[2][3]
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Mechanism of Action
There are multiple pathways and causes of nausea and
vomiting. Specific areas in the brain include the area
that make up a central pattern generator.[4] A complex
interaction of vagal afferents and efferents to the cortex,
hypothalamus, and limbic regions also play a role in how the
brain perceives nausea.[5] Multiple chemoreceptors are
involved in these pathways and include the muscarinic M1,
dopaminergic D2, serotonin 5HT-3, neurokinin-1, and
histamine H-1. As such, most of the anti-emetics can be
broadly classified into the following classes based on the
mechanism of action:
1. Serotonin-receptor antagonists
2. Glucocorticoids
3. Anticholinergics
4. Neurokinin-receptor antagonists (Substance-P)
5. Dopamine receptor antagonists
6. Cannabinoids
7. Antihistamines
8. Other
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Administration
The setting and clinical presentation will dictate the type
of medication prescribed, dosing, and route of
administration. A careful review of the symptoms and past
medical history, allergies, and prior exposure to/uses of these
medications will lead to a better outcome for the patient.
Serotonin-receptor antagonists: Ondansetron, granisetron,
dolasetron, palonosetron. The mechanism of action is to
block serotonin from interacting with the 5HT-3 receptor. Of
these, ondansetron, and granisetron are the most frequently
encountered. Intravenous (IV) and oral (PO) preparations are
available. Side effects include headache, dizziness, and
constipation. The most worrisome side effect is QT-
prolongation, and these medications should be avoided in
patients with known prolonged QTc.
Glucocorticoids: The mechanism of action is unknown.
Dexamethasone has been widely studied in the
chemotherapy and the prevention of postoperative nausea
and vomiting literature. Side effects are mild and include
insomnia, excitation, and changes in mood. PO and IV
formulations are available.[6][7]
Anticholinergics: Scopolamine is the most commonly
encountered medication in this class. It works by
antagonizing the M1 muscarinic receptor. It is predominantly
used to treat motion sickness or prophylactically in the
perioperative setting. Side effects are typically mild but
include dry mouth, vision changes, or drowsiness. It is
administered transdermally.[8]
Neurokinin receptor antagonists: Aprepitant (PO) and
fosaprepitant (IV) highlight this class of medications that
involve antagonism of the NK-1 receptor, preventing the
release of substance-P, which is an inducer of vomiting. As
with many medications, side effects include headache and
dizziness, but case reports have been published noting
significant hypersensitivity reactions to include anaphylaxis
and anaphylactic shock.[9]
Dopamine receptor antagonists: Phenothiazines antagonize
the D2 receptor, most notably in the area postrema in the
brain. Prochlorperazine and chlorpromazine are examples of
this class of medication. IV, PO, and rectal (PR) formulations
are available. Side effects include dizziness, headache and
extrapyramidal symptoms to include dystonia and tardive
dyskinesia.[10]
Butyrophenones also work to antagonize the D2 receptor.
Droperidol and Haloperidol have proven to be very
efficacious anti-emetics, but due to the side effect profiles
have fallen out of favor in many environments. Intramuscular
(IM) and IV are effective routes of administration. In addition
to more typical side effect profiles, these medications can
cause dose-dependent QT prolongation and should be used
with caution in those with known or suspected QTc
prolongation.
Benzamides antagonize the D2 receptor at low doses but also
antagonizes the 5HT-3 receptor at higher doses.
Metoclopramide is the common medicine in this class and is
typically used as a pro-motility agent to reduce nausea and
vomiting. PO and IV formulations are available. This
medication can cross the blood-brain barrier. As with other
dopamine antagonists, this medication can cause dystonia,
tardive dyskinesia, and akathisia. An FDA “Black-Box” warning
from the FDA cautions against repeated, and long-term use as
it can cause irreversible tardive dyskinesia.
Cannabinoids therapy is relatively new and somewhat
controversial. Nabilone and dronabinol have been studied
and show some benefit, though significant side-effects such
as vertigo, hypotension, and dysphoria have limited their use
in some populations. IV and PO formulations are available.[6]
Antihistamines act to antagonize the histamine (H1, H2)
receptors. Diphenhydramine, meclizine, promethazine are
common medications in this class. They are widely available,
generally well tolerated and there are PO, IV, IM, PR
formulations available. Sedation is a widely reported,
common side effect.[11][12]
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Adverse Effects
Generally, anti-emetic medications are well tolerated. As
indicated above, side effects range from more common (mild
headaches and dizziness) to rare (anaphylaxis,
hypersensitivity.) The list of all side effects is beyond the
scope of this document, and the practitioner should review
all possible side-effects (common and uncommon) before
prescribing these medications. However, as noted,
extrapyramidal symptoms to include tardive dyskinesia,
akathisia, and dystonia are well described. QTc prolongation
and subsequent Torsades de Pointes can also be a life-
threatening complication and should be considered when
prescribing these medications.[13]
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Contraindications
Contraindications will vary based on class and mechanism of
medication:
1. Serotonin-receptor antagonists: Known
hypersensitivity. Consider another class if the
patient has prolonged QTc.[14] Serotonin syndrome
has been reported, particularly when used in
conjunction with SSRIs, selective norepinephrine
serotonin reuptake inhibitors (SNRIs), mirtazapine,
monoamine oxidase inhibitors(MAOIs), and other
medications that modulate serotonin levels.
2. Glucocorticoids: Hypersensitivity, systemic fungal
infections.
3. Anticholinergics: Known hypersensitivity, narrow-
angle glaucoma
4. Neurokinin-receptor Antagonists (Substance-
P): Known hypersensitivity
5. Dopamine receptor antagonists: Known
hypersensitivity, use in children younger than 2 or
weighing less than 9 kg. Consider avoiding
medication in comatose patients or those with
depressed GCS. Parkinson, affective disorders, or
those already being treated with medications in this
class.
6. Cannabinoids: Known hypersensitivity
7. Antihistamines: Known hypersensitivity