Category:Antiemetics: Difference between revisions

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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, [[wikipedia:Paul Andrews (pharmacologist)|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.<ref name="andrews1988">Andrews PL, Rapeport WG, Sanger GJ. Neuropharmacology of emesis induced by anti-cancer therapy. ''Trends in Pharmacological Sciences''. 1988 Sep;9(9):334-341. PMID 3074552.</ref> Selective 5-HT3 antagonists were developed in response: [[wikipedia:Ondansetron|ondansetron]] (Glaxo, 1991), [[wikipedia:Granisetron|granisetron]] (SmithKline Beecham, 1993), dolasetron (1997), [[wikipedia:Palonosetron|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 ~~prodrug~~ fosaprepitant (2008) 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 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 ([[wikipedia:Dronabinol|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.

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