The main limitation of metoclopramide is its extrapyramidal side effects (eg, akathisia, dystonia, psuedoparkinsonism, dyskinesia). Akathisias (ie, restlessness) is a particularly common phenomenon in patients taking metoclopramide. Patients experiencing extrapyramidal reactions are typically treated with diphenhydramine. In addition to the extrapyramidal side effects, metoclopramide is relatively contraindicated in patients with complete bowel obstruction.13,17
In addition to metoclopramide, erythromycin and mirtazapine are other prokinetic agents used in palliative care. Erythromycin has mainly been used for diabetic gastroparesis due to its stimulatory effect on motilin receptors in the GI tract.13,23 Mirtazapine is an antidepressant with both 5-HT3 and 5-HT4 receptor activity. In one case report it was used to treat gastroparesis refractory to all other therapies, including metoclopramide and erythromycin.23
Dopamine-Receptor Antagonists
This category includes many agents, most which are known for their antipsychotic effects. The primary mode of action of dopamine-receptor antagonists is to block D2 receptors in the vomiting center. Etiology-based antiemetic treatment guidelines list these drugs as the first choice in patients with a biochemical-based etiology for nausea, though there is little-to-no evidence to support this recommendation.9,10,12,13,17
Chlorpromazine and Prochlorperazine (Pheno thiazines). These D2-receptor antagonists are widely used in palliative care as antiemetics. Due to crossreactivity with adrenergic, serotonergic, histaminic, and cholinergic receptors, they have many side effects, including sedation, hypotension, anticholinergic symptoms, dystonias, extrapyramidal symptoms, psychosis, QT prolongation, neutropenia, and lowered seizure thresholds.13 These side effects, coupled with the chronic shortages of IV prochlorperazine preparations, make them of limited use in the ED.
Haloperidol. This D2-receptor antagonist is a butyrophenone—a purer D2 receptor blocker with less crossreceptor activity. Haloperidol causes less sedation and hypotension than phenothiazines. However, since it exerts more extrapyramidal effects, it should be avoided in patients with Parkinson disease. It can also exacerbate narrow-angle glaucoma.13
While a review on haloperidol use in cancer found its effects better than placebo for CINV and postoperative nausea, studies in the review were small and the evidence weak.24 Due to its low cost, and comparatively favorable side-effect profile, haloperidol is a reasonable alternative to metoclopramide. Indeed, if palliative-care models are used, haloperidol would be preferred over metoclopramide since biochemical nausea is probably more prevalent in the general ED cancer patient than gastroparesis.
Olanzapine. This is an atypical antipsychotic agent with antagonist activity at multiple emetic pathway receptors: D2, 5-HT3, H1, and AChM. The advantages of olanzapine include appetite stimulation, fewer extrapyramidal side effects, and less QT prolongation. It should be used with caution in elderly patients due to sedation and delirium. A recent systematic review of olanzapine found it showed markedly superior efficacy in treating breakthrough vomiting, compared to metoclopramide, prochlorperazine, and dexamethasone. The review states “olanzapine is probably the drug of choice for breakthrough CINV, especially for delayed nausea.”18
Regarding route of administration, olanzapine can be given orally or intramuscularly, making it potentially useful in the ED setting for those who cannot keep pills down and have poor venous access. When used in the supportive care setting, however, olanzapine is typically given at bedtime due to its sedative effects. As such, this agent may be best given to those who will be admitted or placed on observation status, since some patients may not be able to be discharged even if nausea resolves.
Antihistamine Agents
Cyclizine, diphenhydramine, hydroxyzine, meclozine, and promethazine, are all piperazine H1-receptor blockers that work in the vomiting center, vestibular nucleus, and chemoreceptor trigger zone. In addition to its properties as an H1-receptor antagonist, cyclizine also exhibits some anticholinergic activity that decreases bowel secretions, thus making it theoretically beneficial in patients with bowel obstruction. Each of these antihistamines are considered beneficial in treating nausea due to vestibular dysfunction and in motion sickness, and may be helpful in patients with increased ICP. Heavy sedation, anticholinergic, and extrapyramidal side effects may occur with these drugs, especially in elderly patients.1,13,17
Serotonin 5-HT3 Receptor Antagonists
Dolasetron, granisetron, ondansetron, palonosetron, and tropisetron are among the 5-HT3 (serotonin type 3) receptor antagonists used to treat nausea and vomiting. As previously stated, chemotherapy stimulates release of 5-HT from the gut, which in turn stimulates 5-HT3 receptors in the gut, vagus nerve, and the chemotherapy trigger zone—all of which in turn stimulate the vomiting center, leading to the vomiting reflex.1,13,17,19,21 The blocking action of these drugs on the 5-HT3 receptors is the basis of the antiemetic effect. Palonosetron, with its long 40-hour half-life, has become the preferred prophylactic agent for CINV. The most common adverse events with 5-HT3 antagonists include mild headache, transient elevation of hepatic aminotransferase levels, and constipation.19,21 The use of ondansetron for emesis in the ED is becoming more established both for CINV and non-CINV—mainly due to its high efficacy and favorable side-effect profile compared to metoclopramide and the dopamine antagonists.