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. 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.
There are multiple pathways and causes of nausea and vomiting. Specific areas in the brain include the area postrema in the floor of the fourth ventricle, the nucleus tractus solitarius in the medulla, and various motor nuclei that make up a central pattern generator. 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. 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:
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.
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.
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.
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.
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.
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.
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.
Contraindications will vary based on class and mechanism of medication:
Monitoring considerations will be dependent on the clinical environment and patient presentation. It is not typical to measure or use blood levels of any of these medications. Patient-specific monitoring relating to side effects will be specific to the patient the medication received.
A multidisciplinary approach to antiemetics
As described above nausea and vomiting is a common symptom and part of a complex pathway. Selecting the appropriate treatment option will require coordination across all areas of healthcare to include nurses, physicians, pharmacists, and other health professionals. The current level of evidence for treatment varies for each class and specific drug. Some medications have been thoroughly tested through RCTs, sometimes alone, and sometimes, in conjunction with other therapies. Other medications, for example, the cannabinoids, lack an in-depth level of testing and investigation. Interprofessional teams and thoughtful, appropriate, prescribing methods will increase patient safety and improve outcomes.
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