This article overviews the pharmacology of drugs used for the prevention and treatment of chemotherapy induced nausea and vomiting (CINV). A brief introduction on the pathophysiology is presented, to be followed by a discusssion on the different drug classes. At the bottom of the page you can find a PowerPoint presentation on CINV.
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Pathophysiology of chemotherapy induced nausea and vomiting
Chemotherapeutic drugs can trigger emesis by two ways:
- Direct activation of the medullary chemoreceptor trigger zone. 5-HT3 (serotonin 3), D2 (dopamine) and NK-1 receptors play a critical role as neurotransmitters.
- Cell damage of the GI tract. This causes serotonin release from the enterochromaffin cells, this molecule activates 5-HT3 receptors on vagal and splanchnic afferent fibers that send impulses to the medulla, activating the CTZ which stimulates the vomiting center.
Drugs used for CINV treatment and prophylaxis
The rational therapeutic approach to the pathophysiology of CINV includes blockade of the neurotransmitters involved in the triggering of emesis. The image below shows the main pharmacological groups, organized by mechanism of action.
Serotonin 5-HT3-receptor antagonists
5-HT3 antagonists play a key role in the management of CINV.They act through selective blockade of 5-HT receptors in visceral vagal afferent fibers and in the chemoreceptor trigger zone. They are efficacious against all grades of emetogenic therapy. Drugs in this class include: ondansetron, granisetron, palonosetron and dolasetron.
NK-1 receptor blocker
Aprepitant is the first drug in this new family of antiemetic agents. It targets the neurokinin receptor and blocks the actions of the natural substance P. Aprepitant is recommended before chemotherapy of high emetic risk (combined with 5-HT3 blocker and dexamethasone) and moderate emetic risk (combined only with dexamethasone).
Phenothiazines. Prochlorperazine: its main mechanism of action is dopamine D2 receptor antagonism at the chemoreceptor trigger zone. It is effective against low emetogenic chemotherapy, but side effects (hypotension, restlessness, sedation, extrapyramidal symptoms) are dose limiting.
Atypical. Olanzapine has potential antiemetic properties because of its action at multiple receptor sites implicated in the control of nausea and vomiting. MASCC and NCCN guidelines recommend a dose of 2.5–5 mg olanzapine for the treatment of refractory and breakthrough emesis.
Metoclopramide is no longer supported as a first-line agent by the MASCC, ASCO, and NCCN guidelines. Besides, antidopaminergic side effects (sedation, diarrhea, extrapyramidal symptoms) limit use of metoclopramide at high doses. However, metoclopramide has been proven to be as effective as 5-HT3 receptor antagonists when combined with steroids in the prevention of delayed CINV.
Dexamethasone plays a major role in the prevention of acute and delayed CINV and it is an integral component of almost all antiemetic regimens. Corticosteroid antiemetic mechanism remains to be elucidated, it is believed that it may involve blockade of prostaglandins synthesis. Dexamethasone can be administered P.O or IV , and is recommended in combination with aprepitant before highly emetogenic chemotherapy.
Dronabinol and nabilone are effective against moderately emetogenic chemotherapy. Side effects include dysphoria, hallucinations, sedation, vertigo and disorientation. This number of adverse reactions places them as second line agents.
PowerPoint presentation on CINV pharmacology
References and further reading
Navari, R. “Chemotherapy induced Nausea and Vomiting”, 1st edition. Oxford University Press: 2010
Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009