Pharmacokinetics, pharmacodynamics, safety, and tolerability of dopamine-receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting

ABSTRACT

Introduction

Dopamine (D)_2,3-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV).

Areas covered

Eight D_2,3-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects.

Expert opinion

Since the introduction of D_2,3-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)₃-RAs and neurokinin (NK)₁-RAs have been developed. The classical D_2,3-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D_2,3-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.

The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT₃-RA, dexamethasone and a NK₁-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.

Side effects differ among various D_2,3-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D_2,3-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.

KEYWORDS:

• Chemotherapy-induced nausea and vomiting
• dopamine-receptor antagonists
• domperidone
• haloperidol
• metoclopramide
• metopimazine
• olanzapine
• prochlorperazine

Article highlights

• Dopamine-receptor antagonists were the first clinically useful antiemetics for the prophylaxis and treatment of chemotherapy-induced nausea and vomiting (CINV).

• Some of the dopamine-receptor antagonists (e.g. metopimazine, olanzapine) act at other receptors which has a potential impact on both antiemetic effect and side effects.

• Side effects differ among the different dopamine-receptor antagonists, but the most common include extrapyramidal symptoms, prolonged QTc interval and orthostatic hypotension.

• Newer dopamine-receptor antagonists such as olanzapine (acting at multiple other receptors) are effective in CINV treatment and have lower risk of potentially serious side effects.

• Olanzapine is currently the only dopamine-receptor (multiple receptor) antagonist recommended by evidence-based guidelines to be included as a fixed component of an antiemetic regimen for prophylaxis of CINV.

• Metopimazine (also acting at α-adrenergic receptors) is an effective antiemetic, but is not globally available, and amisulpride may be active against CINV as shown in phase 2 studies. However, further studies are necessary.

Declaration of interest

J Herrstedt has received honorarium from Pharmathen S.A. (ad hoc consultancy) and Astellas Pharma (teaching activities). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.