Postoperative nausea and vomiting (PONV) is the most common complication associated with anesthesia and surgery, occurring in approximately one-third of all patients and up to 70% of “high-risk” patients.¹ PONV is a cause of great distress for patients, and in addition to creating a highly unpleasant experience of discomfort, it can lead to a variety of unintended consequences such as delayed discharge, wound dehiscence, dehydration, tearing of sutures, and potential pulmonary aspiration, all of which serve to greatly increase medical costs.² Understanding the various mechanisms involved in PONV is critical for optimizing the prophylaxis and treatment of this unwanted side effect of anesthesia.

There are numerous risk factors associated with the development of PONV, and these can be divided into patient specific risk factors, anesthesia-related factors, and surgery-related factors (Table 15–1). By careful evaluation of an individual’s risk factors for the development of PONV, those who will most likely benefit from prophylactic antiemetic therapy can be more easily identified.

The physiologic process of vomiting (emesis) involves a series of autonomic changes that operate in the brainstem at the level of the medulla oblongata. Within this region of the hindbrain, various afferent sources of emetic input are received by the area postrema, known as the chemoreceptor trigger zone (CTZ), and the vomiting center located in the nucleus tractus solitarius (NTS).³ The signals received by the CTZ and the vomiting center are mediated primarily by major neurotransmitter receptor systems. The major neurotransmitters and receptors that supply signals to the CTZ and vomiting center are serotonin (5-HT3), dopamine (D₂), histamine (H₁), muscarinic acetylcholine, and neurokinin (Figure 15–1). Pharmacologic antiemetic agents that work to block the neurotransmitters involved in the development of emesis have long been the mainstay of prophylaxis and treatment of PONV.

Serotonergic Receptor Antagonists

Serotonin is found in high levels peripherally in the enterochromaffin cells of the gastrointestinal tract as well as in the central nervous system (CNS). In response to noxious or mechanical stimuli, serotonin is released and stimulates vagal afferent neurons that in turn activate the CTZ and vomiting center of the NTS.⁴ The most important serotonin receptor involved in PONV is the 5-HT3 subtype. Antagonism of the 5-HT3 receptor effectively blocks the nausea and vomiting cascade mediated by serotonin, and 5-HT3 antagonists have been proven to be safe and widely used for both prophylaxis and treatment of PONV.

Ondansetron was the first of the 5-HT3 antiemetic drugs to be marketed in the United States, and most of the research available regarding 5-HT3 antagonists involves ondansetron. The recommended effective dose of ondansetron is 4 mg intravenously (IV) for adults, and it has been found to be most efficacious when given at the end of surgery. Ondansetron has been shown to be somewhat more effective at preventing vomiting than preventing nausea, with a number needed to treat (NNT) of 6 for the prevention of vomiting within the first 24 hours postsurgery and an antinausea NNT of 7.⁵

Other 5-HT3 antagonists include dolasetron, granisetron, ramosetron, and tropisetron (ramosetron and tropisetron are not available in the United States). If given at their optimal doses, there is no evidence to support a difference in efficacy between the various 5-HT3 receptor antagonists.⁶ The choice then usually is made based on availability and cost. Ondansetron, which is now available in generic form, is substantially less expensive than other drugs in this class, making it the preferred drug of choice. Most 5-HT3 antagonists are most effective during the early phase of PONV (0–24 hours postsurgery) and are less effective during the late phase. Palonosetron is a novel 5-HT3 antagonist with unique pharmacologic properties, and initial studies have shown a single dose of 0.075 mg IV to be effective at preventing PONV for as long as 3 days postsurgery.⁷

All 5-HT3 receptor antagonists are metabolized by cytochrome P450 in the liver. Ondansetron as well as most other 5-HT3 antagonists are specifically metabolized by the CYP2D6 isoform. Genetic polymorphism of the CYP2D6 isoform influences the metabolism and efficacy of ondansetron, as patients with CYP2D6 deficiency display poor metabolism of the drug (leading to accumulation in the body) and patients with increased CYP2D6 have ultra-rapid metabolism that leads to increased incidence of ondansetron prophylaxis failure.^8,9 The 5-HT3 antagonists are a popular and widely used choice for antiemetic therapy because of their favorable side effect profile. 5-HT3 antagonists have been found to cause constipation, headache, elevated liver enzymes, and asymptomatic QT prolongation, but the number needed to harm (NNH) associated with these side effects is high at 23, 36, and 31 respectively, thus making 5-HT3 antagonists a safe choice for PONV treatment and prevention.⁵

Dopaminergic Receptor Antagonists

D₂ receptor antagonists are a useful class of antiemetics; they successfully block D₂ receptors located in the CTZ. Among the subtypes of D₂ antagonists are the phenothiazines (eg, promethazine, prochlorperazine, chlorpromazine), butyrophenones (eg, droperidol, haloperidol), and benzamides (eg, metoclopramide, domperidone).⁴