Antinausea Medications

Ian N. Olver

Nausea and vomiting can be symptoms associated with cancer, but it was the introduction of cytotoxic chemotherapy of high emetic potential to treat cancer that stimulated research on the mechanisms of emesis. This has resulted in the introduction of two new classes of antiemetics, namely, the 5 hydroxytryptamine 3 receptor antagonists (5HT3 RA) and the neurokinin 1 receptor antagonists (NK1 RA), which have made a major impact on the control of emesis (Table 39-1).

Three distinct types of emesis are associated with chemotherapy. The most common is postchemotherapy emesis occurring in the 24 hours after chemotherapy.¹ Delayed emesis is thought to commence around 18 hours after treatment and can last for at least 5 days.² For patients who experience emesis with chemotherapy, anticipatory emesis can occur with subsequent cycles as a conditioned response.³

The most important predictor of acute postchemotherapy emesis is the type, dose, and schedule of the chemotherapy (Table 39-2). Drugs of high emetic potential have a 90% or greater chance of causing emesis if no antiemetic prophylaxis is given.⁴ The paradigm example is cisplatin, which when given over an hour at greater than 60 mg/m² will cause almost all patients to vomit, and is associated with both acute and delayed emesis. Trials to test new antiemetic drugs frequently focus on cisplatin-induced emesis. Drugs such as anthracyclines or cyclophosphamide have moderate emetic potential (between 30% and 90% chance of emesis). The combination of these drugs (AC) is of high emetic potential, however.

TABLE 39.1 Classes of antiemetics

Drug class	Examples of drugs
Serotonin RA	Ondansetron, Granisetron, Tropisetron, Dolasetron, Palonosetron
Neurokinin RA	Aprepitant, Fosaprepitant, Casopitant
Dopamine RA	Metoclopramide, Metopimazine, Prochlorperazine, Alizapride, Droperidol, Haloperidol
Glucocorticoids	Dexamethasone, Methylprednisolone
Cannabinoids	Nabilone, Dronabinol
Benzodiazepine	Lorazepam, Olanzepine^a
Anticholinergics	Scopolamine
Antihistamines	Diphenhydramine
Miscellaneous	Gabapentin, Ginger
^aOlanzepine is a thienobenzodiazepine acting on multiple receptors.
RA, receptor antagonist.

A number of patient characteristics predict emesis after chemotherapy.⁵ Younger patients are more prone to vomiting than older, as are women compared to men. Patients who have previous vomiting with chemotherapy, or motion sickness, or vomiting with pregnancy are more likely to vomit postchemotherapy. Those patients with a prolonged history of heavy alcohol consumption vomit less after chemotherapy.

Nausea and vomiting are among the most distressing side effects of chemotherapy.⁶,⁷ These side effects are also associated with fatigue, anorexia, and insomnia.⁸ Doctors and nurses tend to underestimate nausea and vomiting, particularly in the delayed phase, which can lead to undertreatment.⁹

5HT3 Receptor Antagonists

The initial revolution in the control of chemotherapy-induced emesis came with the introduction of a new class of antiemetics, the 5HT3 RAs. The antiemetics previously available, such as the substituted benzamides, the phenothiazines, and butyrophenones, had very limited efficacy against chemotherapy-induced emesis and had unpleasant side effects, including somnolence, depression, dysphoria, and tardive dyskinesia.

Mechanistic studies revealed that chemotherapy causes the release of 5-hydroxtryptamine from the enterochromaffin cells in the small intestine. This 5HT stimulates the vagal afferents that connect to the dorsal brainstem, the nucleus tractus solitarius, and the area postrema (Fig. 39-1). Efferent fibers then go to an area known as the central pattern generator more ventrally in the brain stem, and the vomiting reflex is initiated.¹⁰,¹¹ The area postrema also has direct contact with the blood and cerebrospinal fluid, sitting as it does in the floor of the 4th ventricle, and can also be stimulated via that route.

The first of the 5HT3 RAs, ondansetron, when given in combination with dexamethasone before chemotherapy of high emetic potential achieved control of acute postchemotherapy emesis in over 80% of patients with a rate of around 65% if used as a single agent (Fig. 39-2).¹² The side-effect profile was favorable, with the main toxicities being mild headache, constipation, and transient elevation in liver transaminases. Randomized studies and meta-analyses did not demonstrate differences in the therapeutic effect of ondansetron, granisetron, tropisetron, or dolasetron, although in
Jordan’s meta-analysis, there were some differences in subset analyses of the granisetron and tropisetron comparison.¹³,¹⁴

TABLE 39.2 Classification of anticancer drugs based on emetogenic potential

Level 1 (minimal risk, <10%)	Level 2 (low risk, 10%-30%)	Level 3 (moderate risk, 31%-90%)	Level 4 (high risk, >90%)
Bevacizumab	Bortezomib	Carboplatin	Carmustine
Bleomycin	Cetuximab	Cyclophosphamide	Cisplatin
Busulfan	Clofarabine	High-dose Cytarabine (>1 g/m²)	High-dose Cyclophosphamide (>1.5 g/m²)
Cladribine	Cytarabine (<100 mg/m²)	Daunorubicin	Dacarbazine
Fludarabine	Dasatanib	Doxorubicin	Mechlorethamine
Vinblastine	Docetaxel	Epirubicin	Streptozotocin
Vincristine	Etoposide	Idarubicin
Vinorelbine	Fluorouracil	Ifosfamide
	Gemcitabine	Imatinib
	Ibritumomab tiuxetan	Irinotecan
	Ixabepilone	Oxaliplatin
	Lapatanib
	Methotrexate
	Mitomycin
	Mitoxantrone
	Nilotinib
	Paclitaxel
	Pemetrexed
	Procarbazine
	Sorafenib
	Sunitinib
	Temsirolimus
	Topotecan
	Tositumumab
	Trastuzumab

The 5HT3 RAs are metabolized by the liver through hydroxylation followed by glucuronide or sulfate conjugation. The metabolites do not seem to contribute to antiemetic activity. Currently, the 5HT3 RAs are given by single daily dosing rather than the initial multiple day schedules in the original ondansetron studies.¹⁵ Oral formulations have also been shown to be as effective as the intravenous dosing (Table 39-3).¹⁶

The clinical trials of the initial 5HT3 RAs such as ondansetron showed that they demonstrated low efficacy for cisplatin-induced delayed emesis.¹⁷ These first-generation 5HT3 RAs only had modest activity for the delayed emesis associated with chemotherapy of moderate emetic potential.¹⁸

Palonosetron

The initial second-generation 5HT3 RA, palonosetron, has different properties and efficacies than the first-generation 5HT3 RAs (Fig. 39-2). Palonosetron has a mean elimination half-life of approximately 40 hours as compared to 4 to 9 hours with the first-generation 5HT3 RAs, but the same favorable safety profile.¹⁹ It also exhibits a 30-fold higher binding affinity for the receptor than the first-generation drugs. The binding differs in that whereas ondansetron and granisetron show simple bimolecular binding, palonosetron demonstrates allosteric binding with positive cooperativity to inhibit receptor function over a longer time and triggers either inactivation or internalization of the 5HT3 receptor.²⁰

In the early phase studies of palonosetron, the side effects of headache, constipation, and dizziness were similar to other 5HT3 RAs and no cardiac safety issues were noted. Of the first three large phase III trials, two were for chemotherapy of moderate emetic potential, comparing single intravenous doses of palonosetron with ondansetron or dolasetron.²¹,²² Gralla et al.²¹ found that single-dose palonosetron (0.25 and 0.75 mg) was not inferior to ondansetron (32 mg) for the response of no vomiting, no rescue for acute emesis, and was considered superior in the control of delayed emesis. Also there was a suggestion that nausea was better controlled than with the first-generation 5HT3 RAs.²¹ Similarly, Eisenberg et al.²² demonstrated a similar outcome in the comparison of palonosetron with 100 mg of dolasetron. The third trial compared palonosetron with ondansetron in the prophylaxis of chemotherapy of high
emetic potential and showed noninferiority for acute, delayed, and overall emesis.²³

FIGURE 39-1 The emetic response is elicited by signals emanating from a variety of sources including motion, smells, blood-borne toxins, and other signals. These pathways involve a variety of neurotransmitters, including dopamine, acetylcholine, histamine, serotonin (5-hydroxytryptamine), and substance P, among others. Emetic responses can be blocked by agents that interfere with these pathways. Abbreviations: serotonin (5HT); serotonin receptor 3 (5HT3), neurokinin 1 receptor (NK1), dopamine 2 receptor (D2), acetylcholine receptor (M1), histamine 1 receptor (H1).

The next step in the assessment of palonosetron was to evaluate it in combination with both dexamethasone and as part of triple prophylactic antiemetic therapy with dexamethasone and an NK1 RA to ascertain whether palonosetron should replace the older 5HT3 RAs in antiemetic regimens with chemotherapy of high or moderate emetic potential.

A pooled analysis of the two studies with chemotherapy of moderate emetic potential had suggested that although the occurrence of acute chemotherapy-induced nausea and vomiting is the strongest predictor of delayed emesis, the efficacy of palonosetron in the
delayed phase was not just a carryover effect but directly due to the activity of palonosetron.²⁴

FIGURE 39-2 Structure of commonly used 5HT3 RAs.

TABLE 39.3 Dosages and plasma terminal half-lives of selected antiemetics

Drug	Dosing	Half-life^a (hours)
Ondansetron	Oral 24 mg	3-4
	IV 8-32 mg
Granisetron	Oral 2 mg	7
	IV 10 μg/kg
Tropisetron	Oral 5 mg	8
	IV 5 mg
Dolasetron	Oral 100 mg	7-8
	IV 100 mg
Palonosetron	IV 0.25 mg	40
Aprepitant	Oral 125 mg day 1	9
	80 mg day 2 and 3
Fosaprepitant	IV 115 mg	9-13
Casopitant	Single oral 150 mg day 1	9-15
	IV day 1 90 mg then 50 mg oral days 2 and 3
^aTerminal half-life rounded to nearest hour.
IV, intravenous.

Saito et al.²⁵ compared palonosetron and dexamethasone with granisetron and dexamethasone in 1,114 patients receiving chemotherapy of high emetic potential (including the AC combination). The complete response rate for acute emesis was 75.3% in the palonosetron arm versus 73.3% in the granisetron arm of the study.

Small studies have also shown that palonosetron can be safely administered over multiple days. Einhorn et al.²⁶ reported giving palonosetron on days 1, 3, and 5 with dexamethasone at different doses and schedules on days 1, 2, 6, 7, and 8 of a 5-day cisplatin regimen for testicular cancer, while Musso et al.²⁷

Only gold members can continue reading. Log In or Register to continue