Category:Antiemetics

An antiemetic is a medicine used to prevent or treat nausea and vomiting. The category is mechanistically heterogeneous because the emetic reflex is coordinated by the brainstem chemoreceptor trigger zone, which integrates signals from the gut (vagal afferents responding to serotonin released by enterochromaffin cells), from the vestibular system (cholinergic and histaminergic input), from higher centres (limbic inputs in anticipatory and psychogenic nausea), and from circulating substances (acting at the area postrema, where the blood-brain barrier is permeable). Each of these inputs is mediated by characteristic neurotransmitter receptors, and the major antiemetic classes correspond to receptor-antagonist medicines for each: the 5-HT3 antagonists for the gut-vagal pathway, the antihistamines and antimuscarinics for the vestibular pathway, the dopamine D2 antagonists for the area postrema, the neurokinin-1 (NK1) receptor antagonists for the late and delayed component of chemotherapy-induced nausea, the corticosteroids by less well-defined mechanism, the cannabinoid receptor agonists for refractory cases, and the neuroleptics for malignant gastrointestinal emergencies.

The clinical pharmacology of nausea was, until the 1950s, dominated by the antimuscarinic alkaloids of the nightshade family (scopolamine, hyoscyamine, atropine) and by sedating antihistamines (diphenhydramine and its less-sedating successor meclizine; promethazine; dimenhydrinate, a chemical complex of diphenhydramine with 8-chlorotheophylline marketed as Dramamine). These agents, with their substantial central sedation and antimuscarinic toxidrome, remained the standard for motion sickness, for benign vestibular vertigo, and for pregnancy-related nausea until the introduction of more specific receptor antagonists. They have not been replaced for the vestibular indications, where the central anticholinergic action is mechanistically appropriate.

The introduction of the dopamine D2 antagonist metoclopramide (Reglan) in 1964 brought the first non-sedating oral antiemetic with broader applicability. Metoclopramide combines D2 antagonism at the chemoreceptor trigger zone with peripheral prokinetic action on the upper gastrointestinal tract (5-HT4 agonism, weak peripheral D2 antagonism), making it useful in gastroparesis and in refractory nausea of various causes. Its adverse-effect profile is dominated by extrapyramidal phenomena (acute dystonia, akathisia, parkinsonism, and the most-feared tardive dyskinesia after chronic use), and its FDA boxed warning since 2009 has restricted long-term use. The related domperidone (Janssen, 1974), a peripheral D2 antagonist that does not cross the blood-brain barrier and so does not produce extrapyramidal effects, is widely used outside the United States; it was not approved in the U.S. because of a small but real QT-prolongation signal but is available through a compassionate-use programme.

The transformative event of contemporary antiemetic pharmacology was the discovery of the 5-HT3 receptor antagonists. Working in the Glaxo laboratories in the early 1980s, Paul Andrews had shown that cisplatin chemotherapy released serotonin from enterochromaffin cells of the small intestine, and that the released serotonin activated vagal 5-HT3 receptors to produce the severe nausea characteristic of platinum chemotherapy.^[1] Selective 5-HT3 antagonists were developed in response: ondansetron (Glaxo, 1991), granisetron (SmithKline Beecham, 1993), dolasetron (1997), palonosetron (the second-generation, longer-half-life agent, 2003), and the transdermal granisetron patch (Sancuso, 2008). The 5-HT3 antagonists transformed the tolerability of cancer chemotherapy and now define the foundation of the antiemetic regimen for highly emetogenic chemotherapy. Their use has been extended to postoperative nausea (where ondansetron 4 mg intravenous is now routine), to severe gastroenteritis in children, and to refractory nausea in palliative care.

The neurokinin-1 receptor antagonists were the next mechanistic addition. Aprepitant (Merck, 2003), and the longer-acting fosaprepitant (2008, hydrolysed in vivo to aprepitant), and the second-generation rolapitant and netupitant, block the substance P / NK1 receptor in the brainstem and reduce both acute and (more importantly) delayed chemotherapy-induced nausea. The triplet combination of an NK1 antagonist, a 5-HT3 antagonist, and dexamethasone is the standard premedication for highly emetogenic chemotherapy regimens; the addition of olanzapine (a neuroleptic with broad receptor coverage including D2, 5-HT2, H1, and muscarinic) further improves control in the most emetogenic regimens. The exact mechanism by which corticosteroids are antiemetic remains incompletely understood; the effect is empirically established and is the reason dexamethasone is included in essentially every contemporary chemotherapy-antiemetic regimen.

The cannabinoid receptor agonists (dronabinol, a synthetic delta-9-THC oral capsule; nabilone, a synthetic cannabinoid analogue) are used for chemotherapy-induced nausea refractory to first-line agents and for HIV-related anorexia. The selected cases of refractory nausea, particularly in palliative care and in cyclic vomiting syndrome, are treated with low-dose olanzapine or with the neuroleptic haloperidol. The pregnancy-specific antiemetic doxylamine-pyridoxine (Bendectin in the 1970s, withdrawn after litigation in 1983 despite the absence of teratogenicity, reintroduced as Diclegis / Bonjesta in 2013) is the standard first-line for nausea of pregnancy in the United States.

By receptor target:

• 5-HT3 receptor antagonists: ondansetron, granisetron, dolasetron, palonosetron (second-generation, longer half-life)
• Dopamine D2 antagonists (cross-indexed under dopamine D2 antagonists): metoclopramide (also indexed under prokinetics); domperidone (peripheral-only D2); prochlorperazine and chlorpromazine and the older phenothiazine antiemetics; haloperidol (for refractory or palliative-care nausea)
• Neurokinin-1 (NK1) receptor antagonists: aprepitant, fosaprepitant, rolapitant, netupitant (often as fixed combination netupitant-palonosetron, Akynzeo)
• Antihistamines (H1 antagonists for vestibular and motion-sickness indications; cross-indexed under antihistamines): diphenhydramine, dimenhydrinate, meclizine, promethazine, cyclizine, hydroxyzine
• Antimuscarinics (for vestibular and motion-sickness indications; cross-indexed under antimuscarinics): transdermal scopolamine
• Corticosteroids (cross-indexed): dexamethasone, the foundation of CINV regimens at 8 to 12 mg per cycle
• Atypical neuroleptics (broad receptor coverage; cross-indexed under neuroleptics): olanzapine, particularly for highly emetogenic chemotherapy
• Cannabinoid agonists (synthetic): dronabinol, nabilone
• Pregnancy-specific: doxylamine-pyridoxine (Bendectin history, current Diclegis/Bonjesta), with vitamin B6 (pyridoxine) monotherapy as an alternative; metoclopramide and ondansetron in selected pregnancy cases (with ondansetron use in the first trimester remaining controversial)

The boundary of this category is "medicine prescribed primarily to prevent or treat nausea and vomiting." The medicines used to treat the underlying cause of nausea (the antimigraine agents in migraine-associated nausea; the migraine prophylaxis medicines; the antibacterials in gastroenteritis-associated nausea where antibacterial treatment is indicated; the prokinetics in gastroparesis-associated nausea) are listed under their primary indications. The medicines that may reduce nausea as a side effect of their primary action (selected antidepressants in the management of functional dyspepsia; gabapentin for refractory nausea; benzodiazepines in anticipatory nausea) are listed under their primary class. The intravenous fluid replacement for the dehydration that accompanies severe vomiting is supportive care rather than antiemetic and is listed under electrolyte replacements.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.