Continuing Education Activity

Nausea is a commonly encountered symptom in healthcare 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 by motion, medications, anesthesia, position, stress, pregnancy, psychiatric disorder, or fear. Multiple or single neurohumoral pathways may be involved. Indications for the treatment of symptoms require astute evaluation by the treating provider. This activity reviews the indications, contraindications, activity, adverse events, and other critical elements of antiemetic therapy in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients who experience nausea and vomiting as part of a clinical presentation.

Objectives:

• Identify the various possible etiologies requiring antiemetic therapy.

• Determine the mechanism of action of various antiemetic medications.

• Assess the potential adverse events for various antiemetic medications.

• Communicate the role of interprofessional coordination in guiding patient care when antiemetics are part of the patient's therapy to achieve optimal outcomes.

Indications

Nausea is a common symptom in healthcare 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 by motion, medications, anesthesia, position, stress, pregnancy, psychiatric disorder, or fear. Multiple or single neurohumoral pathways may be involved. Indications for the treatment of symptoms require 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 or 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 multifactorial, necessitate more prolonged therapy, and might be more challenging to treat. No rule of thumb can be applied when treating nausea. Empiric treatment of nausea without a clear diagnosis is typically well-tolerated and may significantly benefit the patient. Practitioners should be wary of overlooking surgical emergencies such as small bowel obstructions, perforated viscus, and acute appendicitis, among others. Pregnancy merits consideration in women of childbearing age.[2][3]

Mechanism of Action

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.[4] A complex interaction of vagal afferents and efferents to the cortex, hypothalamus, and limbic regions also influences how the brain perceives nausea.[5] Multiple chemoreceptors are involved in these pathways, including the muscarinic M1, dopaminergic D2, serotonin 5-HT3, neurokinin-1 (NK-1), and histamine H1. As such, most of the antiemetics can broadly fit into the following classes based on the mechanism of action:

• Serotonin-receptor antagonists
• Glucocorticoids
• Anticholinergics
• NK-receptor antagonists (substance-P)
• Dopamine receptor antagonists
• Cannabinoids
• Antihistamines
• Other

Administration

The setting and clinical presentation will dictate the type of medication prescribed, the dosing, and the route of administration. A careful review of the symptoms and past medical history, allergies, and prior exposure to or use of these medications will lead to a better outcome for the patient.

Serotonin-receptor antagonists

These include ondansetron, granisetron, dolasetron, and palonosetron. The mechanism of action is to block serotonin from interacting with the 5-HT3 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 QTc-prolongation, and clinicians should avoid these medications in patients with known prolonged QTc.

Glucocorticoids

The mechanism of action is not clearly understood. Possible mechanisms are changes in the blood-brain barrier and decreased synthesis of prostaglandin messengers. Dexamethasone has been the topic of extensive study in chemotherapy and the prevention of postoperative nausea and vomiting literature. Side effects are mild when used short-term, including insomnia, excitation, and mood changes. 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. The administration is transdermal.[8]

NK 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, an inducer of vomiting. As with many medications, side effects include headaches and dizziness, but published case reports note significant hypersensitivity reactions, including anaphylaxis and anaphylactic shock.[9]

Dopamine receptor antagonists

Phenothiazines antagonize the D2 receptor, most notably in the area of 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, including dystonia and tardive dyskinesia.[10]

Butyrophenones

These agents also work to antagonize the D2 receptor. Droperidol and Haloperidol have proven to be very efficacious antiemetics, but due to their side effect profiles, they 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 QTc prolongation and require caution in those with known or suspected QTc prolongation.

Benzamides

Agents in this drug class antagonize the D2 receptor at low doses but also antagonize the 5-HT3 receptor at higher doses. Metoclopramide is the most common medicine in this class and is typically used as a promotility 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 boxed warning cautions against repeated and long-term use as it can cause irreversible tardive dyskinesia.

Cannabinoid therapy

This 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

These drugs antagonize the histamine (H1, H2) receptors. Diphenhydramine, meclizine, and promethazine are common medications in this class. They are widely available and generally well-tolerated, and PO, IV, IM, and PR formulations are available. Sedation is a widely reported, common side effect.[11][12]

Adverse Effects

Generally, antiemetic 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, including 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]

Contraindications

Contraindications will vary based on class and mechanism of medication:

• Serotonin-receptor antagonists: Known hypersensitivity; consider another class if the patient has prolonged QTc.[14] There are reports of serotonin syndrome, particularly when used in conjunction with selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine serotonin reuptake inhibitors (SNRIs), mirtazapine, monoamine oxidase inhibitors(MAOIs), and other medications that modulate serotonin concentrations.
• Glucocorticoids: Hypersensitivity, systemic fungal infections
• Anticholinergics: Known hypersensitivity, narrow-angle glaucoma
• NK-receptor Antagonists (Substance P): Known hypersensitivity
• Dopamine receptor antagonists: Known hypersensitivity, used in children younger than 2 or weighing less than 9 kg; consider avoiding medication in comatose patients or those with depressed Glasgow coma scale, Parkinson disease, affective disorders, or those already being treated with drugs in this class.
• Cannabinoids: Known hypersensitivity
• Antihistamines: Known hypersensitivity

Monitoring

Monitoring considerations will be dependent on the clinical environment and patient presentation. Measuring or using blood concentrations of any of these medications is not typical. Patient-specific monitoring relating to side effects will be specific to the patient the drug received.

Enhancing Healthcare Team Outcomes

An interprofessional team approach to antiemetics is the best course of action. As described above, nausea and vomiting are common symptoms and part of a complex pathway. Selecting the appropriate treatment option will require coordination across all areas of healthcare, including MDs, DOs, NPs, PAs, nursing staff, pharmacists, and other health professionals. The prescriber would do well to include the pharmacist during agent selection and have the pharmacist perform thorough medication reconciliation and verify dosing and duration. Clinicians can provide counsel on administration, warn about potential side effects (reinforced by the pharmacist), and answer patient questions. They can also verify therapeutic effectiveness on follow-up visits. This interprofessional team methodology will benefit the patient by increasing positive outcomes and minimizing adverse effects. 

The current evidence for treatment varies for each class and specific drug. Some medications have been thoroughly tested through randomized clinical trials, sometimes alone and sometimes in conjunction with other therapies. Other medications, such as cannabinoids, lack an in-depth level of testing and investigation. Interprofessional teams and thoughtful, appropriate prescribing methods will improve patient safety and outcomes.