Scopolamine is a muscarinic anticholinergic drug that readily crosses the blood-brain barrier. In the CNS, it suppresses the emetic response to vestibular stimulation, one of the mechanisms of PONV. Typically, it is administered transcutaneously via a patch applied several hours prior to surgery. The patch formulation reaches peak effectiveness in 4 h and delivers approximately 1 mg of scopolamine over 72 h.

Dose-limiting side effects include dry mouth, mydriasis (leading to blurred vision), decreased gastrointestinal motility, urinary retention, and sedation/amnesia. Blockade of muscarinic receptors in the stomach delays gastric emptying and may increase gastric volume. Concern exists about administering anticholinergic drugs to patients with open-angle glaucoma due to the possibility of creating acute angle-closure glaucoma—an ophthalmologic emergency. Caution should also be used in elderly patients, as they are at increased risk for delirium from centrally acting anticholinergic drugs.

Diphenhydramine and promethazine both have antihistamine effects and are thought to act via blockade of H₁ histamine receptors in the chemoreceptor trigger zone (CTZ). They both also exert anticholinergic effects similar to scopolamine, producing sedative and anti-emetic effects. Diphenhydramine has also been shown to decrease the nausea associated with opioid administration.

Several classes of drugs exert common antagonist effects at D₂ receptors in the chemoreceptor trigger zone (CTZ). These include the phenothiazines, the butryophenones (haloperidol and droperidol), and metoclopramide. This antagonism reduces both the sensation of nausea and actual vomiting. Metoclopramide’s effect may largely lie outside the CNS, however, as it exerts a prokinetic cholinergic effect on the gastrointestinal tract.

Caution should be used when choosing these drugs. They should not be used in patients with Parkinson’s disease, restless legs syndrome, or other movement disorders as they can interfere with drug therapy and prompt exacerbations of these conditions. Extrapyramidal effects (dystonia, akathisia) can limit these drugs’ usefulness and may be very troublesome to patients. Other effects include sedation and orthostatic hypotension. Prolonged use of metoclopramide (3 months or longer) has been associated with tardive dyskinesia. Its short-term perioperative use, however, does not appear to carry this risk.

Much attention has been devoted to the effect of droperidol (and, to a lesser extent, haloperidol) on the QTc interval. Droperidol (along with many other drugs) inhibits the delayed inward rectifier (I_Kr) potassium current in cardiac myocytes, thus prolonging the QTc interval and rendering the myocardium more vulnerable to arrhythmias. Due to reports of torsades de pointes (TdP) in patients receiving larger doses of droperidol (such as for neuroleptanalgesia), the U.S. Food and Drug Administration (FDA) requires a “black box” warning on droperidol, including the requirement for cardiac monitoring for 4 h after drug administration. There has been much debate about the validity of this warning in light of the low doses of droperidol used for PONV prophylaxis (commonly less than 1.25 mg), its proven efficacy, and clinical evidence that supports droperidol’s safety in low doses [3].

Corticosteroids (usually dexamethasone) are commonly used for PONV prophylaxis. Dexamethasone (typically 4–8 mg intravenous [IV]) has been demonstrated to reduce the risk of PONV as well as decrease postoperative pain. Dexamethasone’s mechanism of action is not clear. It is presumed that it exerts anti-inflammatory effects in the CNS and peripherally to reduce inflammatory cytokine production.

A single perioperative dose of dexamethasone is generally well tolerated. Reported adverse effects include hyperglycemia, mood effects, headache, and edema. Hyperglycemia is unlikely in patients with normal glucose metabolism, however. The risk-benefit balance appears to support the perioperative use of dexamethasone, as no convincing evidence of increased risk of surgical site infection exists.

The most commonly used drugs in this category include dolasetron, granisetron, and ondansetron. They bind to and inhibit activation of serotonergic receptors in the gastrointestinal tract, the solitary tract nucleus, and the CTZ. They are significantly more effective in preventing vomiting than nausea. No differences in efficacy or toxicity among the 3 drugs have been demonstrated at clinically used doses (dolasetron 12.5 mg, granisetron 0.35–3 mg, and ondansetron 4 mg). Contrary to many other prophylactic drugs, these agents are usually administered at the end of surgery. The second generation 5-HT₃ antagonist palonosetron (usual dose 0.075 mg), however, is administered at the start of surgery due to its much longer half-life (40 h). Palonosetron also appears to be more effective in preventing PONV than the first-generation drugs.

The 5-HT₃ antagonists are generally well tolerated. The most common side effect is mild headache (15–20%) followed by dizziness (10%). QTc prolongation also occurs with the first-generation drugs but not palonosetron. There have been case reports of TdP in patients receiving first-generation 5-HT₃ antagonists. These drugs do not carry the black box warning that droperidol has, but the FDA does recommend cardiac monitoring for patients with electrolyte abnormalities or patients who are receiving other QTc-prolonging medications. These medications should also be used very cautiously (if at all) in patients taking class III antiarrhythmics such as dofetilide due to the risk of TdP.

Substance P is a neuropeptide with a wide distribution in the CNS. It is found in particularly high concentrations in neurons innervating the solitary tract nucleus and CTZ. Acting through neurokinin type 1 (NK₁) receptors, it affects many functions including regulation of nausea and vomiting. The NK₁ receptor antagonist aprepitant was originally demonstrated to reduce delayed chemotherapy-induced nausea and vomiting. It has also been demonstrated to be an effective and long-lasting prophylactic antiemetic (40 mg PO 3 h prior to surgery) but, due to its slow onset and oral administration, it is not an effective rescue medication. Common side effects of aprepitant include fatigue, abdominal pain, and diarrhea.

Caution is warranted with aprepitant because it is a moderate inhibitor of CYP3A4. Dexamethasone is a substrate of this enzyme and many clinical trials used reduced doses of dexamethasone in combination with aprepitant. Other subtrates of CYP3A4 include macrolide antibiotics, many chemotherapeutic agents, opioids (including fentanyl), benzodiazepines (including midazolam), calcium channel blockers, statins, warfarin, and oral contraceptives. This long list of drug interactions, combined with high acquisition cost, has dampened enthusiasm for aprepitant’s perioperative use.

In addition to its effects on anxiety, prophylactic midazolam (50 mcg/kg IV with induction of anesthesia) has also been shown to reduce the incidence of PONV compared to placebo.