Introduction
The act of emesis and the sensation of nausea that accompanies it generally are viewed as protective reflexes that serve to rid the stomach and intestine of toxic substances and prevent their further ingestion. Vomiting is a complex process that consists of a pre-ejection phase (gastric relaxation and retroperistalsis), retching (rhythmic action of respiratory muscles preceding vomiting and consisting of contraction of abdominal and intercostal muscles and diaphragm against a closed glottis), and ejection (intense contraction of the abdominal muscles and relaxation of the upper esophageal sphincter). This is accompanied by multiple autonomic phenomena including salivation, shivering, and vasomotor changes. During prolonged episodes, marked behavioral changes including lethargy, depression, and withdrawal may occur.
The process appears to be coordinated by a central emesis center in the lateral reticular formation of the mid-brainstem adjacent to both the chemoreceptor trigger zone (CTZ) in the area postrema (AP) at the bottom of the fourth ventricle and the solitary tract nucleus (STN) of the vagus nerve. The lack of a blood-brain barrier allows the CTZ to monitor blood and cerebrospinal fluid constantly for toxic substances and to relay information to the emesis center to trigger nausea and vomiting. The emesis center also receives information from the gut, principally by the vagus nerve (via the STN) but also by splanchnic afferents via the spinal cord. Two other important inputs to the emesis center come from the cerebral cortex (particularly in anticipatory nausea or vomiting) and the vestibular apparatus (in motion sickness). In turn, the center sends out efferents to the nuclei responsible for respiratory, salivary, and vasomotor activity, as well as to striated and smooth muscle involved in the act. The CTZ has high concentrations of receptors for serotonin (5-HT3), dopamine (D2), and opioids, while the STN is rich in receptors for enkephalin, histamine, and ACh, and also contains 5-HT3 receptors. A variety of these neurotransmitters are involved in nausea and vomiting.
Antiemetics generally are classified according to the predominant receptor on which they are proposed to act. However, considerable overlap among these mechanisms exists, particularly for the older agent. For treatment and prevention of the nausea and emesis associated with cancer chemotherapy, several antiemetic agents from different pharmacological classes may be used in combination.
5-HT3-Receptor Antagonists
Examples
- Ondansetron
- granisetron
- dolasetron
- palonosetron
- tropisetron
Ondansetron (ZOFRAN) is the prototypical drug in this class. Since their introduction in the early 1990s, the 5-HT3-receptor antagonists have become the most widely used drugs for chemotherapy-induced emesis. Other agents in this class include granisetron (KYTRIL), dolasetron (ANZEMET), palonosetron (ALOXI; intravenous use only) and tropisetron . The differences among these agents are related mainly to their chemical structures, 5-HT3 receptor affinities, and pharmacokinetic profiles .
There is evidence that effects at peripheral and central sites contribute to the efficacy of these agents. 5-HT3 receptors are present in several critical sites involved in emesis, including vagal afferents, the STN (which receives signals from vagal afferents), and the area postrema itself . Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. Experimentally, vagotomy has been shown to prevent cisplatin-induced emesis. However, the highest concentrations of 5-HT3 receptors in the CNS are found in the STN and CTZ, and antagonists of 5-HT3 receptors also may suppress nausea and vomiting by acting at these sites.
Pharmacokinetics.
The antiemetic effects of these drugs persist long after they disappear from the circulation, suggesting their continuing interaction at the receptor level. In fact, all of these drugs can be administered effectively just once a day.
These agents are absorbed well from the GI tract. Ondansetron is extensively metabolized in the liver by CYP1A2, CYP2D6, and CYP3A4, followed by glucuronide or sulfate conjugation. Patients with hepatic dysfunction have reduced plasma clearance, and some adjustment in the dosage is advisable. Although ondansetron clearance also is reduced in elderly patients, no adjustment in dosage for age is recommended. Granisetron also is metabolized predominantly by the liver, a process that appears to involve the CYP3A family, as it is inhibited by ketoconazole. Dolasetron is converted rapidly by plasma carbonyl reductase to its active metabolite, hydrodolasetron. A portion of this compound then undergoes subsequent biotransformation by CYP2D6 and CYP3A4 in the liver, while about one-third of it is excreted unchanged in the urine. Palonosetron is metabolized principally by CYP2D6 and excreted in the urine as the metabolized and the unchanged form in about equal proportions.
Therapeutic Use
These agents are most effective in treating chemotherapy-induced nausea and in treating nausea secondary to upper abdominal irradiation, where all three agents appear to be equally efficacious. They also are effective against hyperemesis of pregnancy, and to a lesser degree, postoperative nausea, but not against motion sickness. Unlike other agents in this class, palonosetron also may be helpful in delayed emesis , perhaps a reflection of its long half-life.
Adverse Effects
In general, these drugs are very well tolerated, with the most common adverse effects being constipation or diarrhea, headache, and light-headedness. As a class, these agents have been shown experimentally to induce minor electrocardiographic changes, but these are not expected to be clinically significant in most cases.
Dopamine-Receptor Antagonists
Phenothiazines such as prochlorperazine, thiethylperazine, and chlorpromazine are among the most commonly used “general purpose” antinauseants and antiemetics. Their effects in this regard are complex, but their principal mechanism of action is dopamine D2 receptor antagonism at the CTZ. Compared to metoclopramide or ondansetron, these drugs do not appear to be as uniformly effective in cancer chemotherapy-induced emesis. On the other hand, they also possess antihistaminic and anticholinergic activities, which are of value in other forms of nausea, such as motion sickness.
Antihistamines
Histamine H1-receptor antagonists are primarily useful for motion sickness and postoperative emesis. They act on vestibular afferents and within the brainstem. Cyclizine, hydroxyzine, promethazine, and diphenhydramine are examples of this class of agents. Cyclizine has additional anticholinergic effects that may be useful for patients with abdominal cancer.
Anticholinergic Agents
The most commonly used muscarinic receptor antagonist is scopolamine (hyoscine), which can be injected as the hydrobromide, but usually is administered as the free base in the form of a transdermal patch (TRANSDERM-SCOP). Its principal utility is in the prevention and treatment of motion sickness, although it has been shown to have some activity in postoperative nausea and vomiting, as well. In general, anticholinergic agents have no role in chemotherapy-induced nausea
Dronabinol
Dronabinol (delta-9-tetrahydrocannabinol; MARINOL) is a naturally occurring cannabinoid that can be synthesized chemically or extracted from the marijuana plant, Cannabis sativa. The exact mechanism of the antiemetic action of dronabinol is unknown but probably relates to stimulation of the CB1 subtype of cannabinoid receptors on neurons in and around the vomiting center.
Pharmacokinetics
Dronabinol is a highly lipid-soluble compound that is absorbed readily after oral administration; its onset of action occurs within an hour, and peak levels are achieved within 2 to 4 hours. It undergoes extensive first-pass metabolism with limited systemic bioavailability after single doses (only 10% to 20%). Active and inactive metabolites are formed in the liver; the principal active metabolite is 11-OH-delta-9-tetrahydrocannabinol. These metabolites are excreted primarily via the biliary-fecal route, with only 10% to 15% excreted in the urine. Both dronabinol and its metabolites are highly bound (95%) to plasma proteins. Because of its large volume of distribution, a single dose of dronabinol can result in detectable levels of metabolites for several weeks.
Therapeutic Use
Dronabinol is a useful prophylactic agent in patients receiving cancer chemotherapy when other antiemetic medications are not effective. It also can stimulate appetite and has been used in patients with acquired immunodeficiency syndrome (AIDS) and anorexia. As an antiemetic agent, it is administered at an initial dose of 5 mg/m2 given 1 to 3 hours before chemotherapy and then every 2 to 4 hours afterward for a total of four to six doses. If this is not adequate, incremental increases in dose can be made up to a maximum of 15 mg/m2. For other indications, the usual starting dose is 2.5 mg twice a day; this can be titrated up to 20 mg a day.
Adverse Effects
Dronabinol has complex effects on the CNS, including a prominent central sympathomimetic activity. This can lead to palpitations, tachycardia, vasodilation, hypotension, and conjunctival injection (bloodshot eyes). Patient supervision is necessary because marijuana-like “highs” (e.g., euphoria, somnolence, detachment, dizziness, anxiety, nervousness, panic, etc.) can occur, as can more disturbing effects such as paranoid reactions and thinking abnormalities. After abrupt withdrawal of dronabinol, an abstinence syndrome manifest by irritability, insomnia, and restlessness can occur. Because of its high affinity for plasma proteins, dronabinol can displace other plasma protein-bound drugs, whose doses may have to be adjusted as a consequence. Dronabinol should be prescribed with great caution to persons with a history of substance abuse (alcohol, drugs) because it also may be abused by these patients.
Glucocorticoids and Antiinflammatory Agents
Glucocorticoids such as dexamethasone can be useful adjunct in the treatment of nausea in patients with widespread cancer, possibly by suppressing peritumoral inflammation and prostaglandin production. A similar mechanism has been invoked to explain beneficial effects of nonsteroidal antiinflammatory drugs in the nausea and vomiting induced by systemic irradiation.
Benzodiazepines
Benzodiazepines, such as lorazepam and alprazolam, by themselves are not very effective antiemetics, but their sedative, amnesic, and anti-anxiety effects can be helpful in reducing the anticipatory component of nausea and vomiting in patients.
Substance P Receptor Antagonists
The nausea and vomiting associated with cisplatin has two components: an acute phase that universally is experienced (within 24 hours after chemotherapy) and a delayed phase that affects only some patients (on days 2 to 5). 5-HT receptor antagonists are not very effective against delayed emesis. Antagonists of the NK1 receptors for substance P, such as aprepitant (EMEND), have antiemetic effects in delayed nausea and improve the efficacy of standard antiemetic regimens in patients receiving multiple cycles of chemotherapy. Substance P belongs to the tachykinin family of neurotransmitters and is in vagal afferent fibers innervating the STN and area postrema. The tachykinins represent a novel, promising target for new antinauseant drugs.
After absorption, aprepitant is bound extensively to plasma proteins (95%); it is metabolized avidly, primarily by hepatic CYP3A4, and is excreted in the stools; its half-life is 9 to 13 hours. Aprepitant has the potential to interact with other substrates of CYP3A4, requiring adjustment of other drugs, including dexamethasone, methylprednisolone (whose dose may need to be reduced by 50%), and warfarin. Aprepitant is contraindicated in patients on cisapride (see above) or pimozide, in whom life-threatening QT prolongation has been reported.
Aprepitant is supplied in 80- and 125-mg capsules and is administered for 3 days in conjunction with highly emetogenic chemotherapy along with a 5-HT3-receptor antagonist and a corticosteroid. The recommended adult dosage of aprepitant is 125 mg administered 1 hour before chemotherapy on day one, followed by 80 mg once daily in the morning on days 2 and 3 of the treatment regimen.
Conclusion
The discovery of the 5-HT3 receptor antagonists has led to a major advance in the treatment of nausea and vomiting, especially in the postchemotherapy and postoperative settings. Anticholinergics are most effective in motion sickness. Antihistamines and related drugs still are useful for empiric treatment of nausea from a variety of causes. Dronabinol may be an effective agent for more refractory cases. The clinical utility of newer agents such as aprepitant in situations other than postchemotherapy nausea will be tested in coming years.