CASE 31

A 67-year-old woman is receiving chemotherapy for metastatic ovarian cancer. She is on her fourth cycle of a multidrug regimen, including cisplatin and doxorubicin. She has developed nausea and vomiting, among other side effects. You decide to premedicate her with intravenous (IV) ondansetron prior to her next dose of chemotherapy and provide oral ondansetron for home use as well.

What is the mechanism of action of ondansetron?

What are the common side effects associated with ondansetron?

ANSWERS TO CASE 31:

Antiemetics

Summary: A 67-year-old woman has chemotherapy-induced nausea and vomiting and is prescribed ondansetron.

Mechanism of action of ondansetron: Serotonin (5-HT₃)-receptor antagonist in the central nervous system (CNS) and gastrointestinal (GI) tract.

Side effects of ondansetron: Headache, diarrhea, dizziness, agitation.

CLINICAL CORRELATION

Nausea and vomiting are frequent side effects of cancer chemotherapy. Control of these symptoms is an important adjunct to chemotherapy. Several agents with varied mechanisms of action are available. The serotonin (5-HT₃) receptor system in the CNS and GI tract is felt to be a major trigger of chemotherapy-induced nausea and vomiting. Ondansetron and granisetron are specific 5-HT₃-receptor antagonists that are widely used for the treatment of this problem. Granisetron has a higher receptor affinity, is longer acting, and is more potent than ondansetron. Both drugs can be administered intravenously or orally. Metoclopramide, which is primarily a dopamine antagonist, will also antagonize the 5-HT₃ receptor when given in high doses. Metoclopramide also blocks receptors in the chemoreceptor trigger zone (CTZ) in the brain that contribute to nausea. Metoclopramide sensitizes the GI tract to acetylcholine (ACh) activity, which increases GI motility and gastric emptying. It is somewhat less effective for chemotherapy-induced vomiting than ondansetron or granisetron and has the potential for extrapyramidal side effects that are seen with dopamine antagonists.

APPROACH TO:

Pharmacology of Antiemetic Agents

OBJECTIVES

1. List the therapeutic uses of antiemetic medications.

2. Describe the mechanism of action of the antiemetic medications.

3. Describe the adverse effects of the antiemetic medications.

DEFINITIONS

Emesis: Vomiting; a complex reflex that results in forceful emptying of the contents of the stomach through the mouth and sometime the nose.

DISCUSSION

Class

Vomiting is a complex reflex controlled by the vomiting center in the lateral reticular formation of the medulla. The vomiting center has five primary afferents (see Figure 31–1):

Figure 31–1. Primary afferent components to the vomiting center.

1. The CTZ is located outside the blood-brain barrier and is exposed to blood-borne and cerebrospinal fluid emetogenic chemicals. Primary receptors associated with emesis are dopamine D₂, 5-HT₃, neurokinin-1 (NK₁, substance P) and opioid receptors.

2. The vestibular apparatus is located in the inner ear, sending afferents pertaining to motion. Primary receptors are histamine H₁ and muscarinic cholinoreceptors.

3. The pharynx via the vagus nerve sends afferents of the gag reflex.

4. Enteric afferents arise from the GI tract. 5-HT₃ receptors play an important role in these signals.

5. Cerebral cortical afferents with information such as stress, anticipation, psychiatric disorders.

Current antiemetic therapy blocks one or more of these afferents to reduce the activity in the vomiting center.

Serotonin 5-HT₃ Antagonists Selective 5-HT₃ antagonists are potent antiemetic agents for emetogenic signals arising in the GI tract and from the CTZ. These agents are especially useful for nausea from chemotherapeutic agents and for postoperative- or postradiation-induced vomiting. 5-HT₃ antagonists are not useful for motion sickness or nausea of vertigo. Four agents are currently available: ondansetron, granisetron, palonosetron, and dolasetron. They are all administered intravenously; ondansetron and dolasetron can also be administered orally. These agents are most effective if given 30 minutes prior to chemo- or radiotherapy. Oral agents may be administered once or twice daily. 5-HT₃ antagonists have been associated with QT prolongation.

NK₁ receptor antagonists, aprepitant and fosaprepitant, have made a significant improvement in the treatment of patients receiving highly emetic chemotherapy. The NK₁ antagonists are effective as sole agents and have been combined with 5HT₃ antagonists or dexamethasone. Combination treatment is first choice for cancer-induced nausea and vomiting.

Dopamine Antagonists Droperidol is an antipsychotic butyrophenone that has significant antiemetic actions. Its antiemetic properties are mediated by blocking dopamine receptors in the CTZ and in the vomiting center. Droperidol has been associated with a risk of QT prolongation, ventricular tachycardia, and torsade de pointes. Phenothiazines such as promethazine and prochlorperazine block dopamine, histamine, and muscarinic receptors in the same regions. All are useful for treating nausea and vomiting postoperatively but are very sedating.

Extrapyramidal effects and hypotension have been reported.

Metoclopramide is a prokinetic agent that also has antiemetic actions based on its dopaminergic antagonist activity. It may be administered orally or parenterally for nausea following chemotherapy or for postoperative nausea. As with the other dopamine antagonists, side effects are rare but may include extrapyramidal effects: dystonias and Parkinson syndrome may appear days to months after treatment.

Corticosteroids Glucocorticoids such as dexamethasone and prednisolone are used to treat nausea and vomiting associated with chemotherapy. They are most frequently used in combination with other antiemetics. The molecular basis for the antiemetic action of glucocorticoids is not understood.

Antihistamines First-generation antihistamines such as cyclizine, diphenhydramine, and dimenhydrinate are useful to treat nausea associated with motion sickness and vertigo. They are able to penetrate the blood-brain barrier and their action is most likely to decrease afferents from the vestibular apparatus. The most common adverse effect of these agents is sedation.

Anticholinergic Agents Scopolamine is the most effective agent for treating nausea associated with motion sickness or vertigo. It is not effective for nausea of chemotherapy. It is administered via a transdermal patch that delivers drug at a uniform rate for up to 72 hours. By avoiding the peak levels associated with oral administration, incidence of side effects is also reduced. Scopolamine reduces afferents from the vestibular apparatus and decreases the excitability of the labyrinthine receptors. Side effects, typical of antimuscarinic agents, include dry mouth, blurred vision, and drowsiness. It should not be used in patients with glaucoma or prostatic hypertrophy.

Other Agents Used as Antiemetics Benzodiazepines such as lorazepam or diazepam may be used prior to chemo- or radiotherapy to reduce the frequency and severity of anticipatory vomiting that occurs in patients who undergo multiple rounds of anticancer therapy. Dronabinol is Δ⁹-tetrahydrocannabinol, the major active ingredient in marijuana. It is an orally active agent that has been used to stimulate appetite and as an antiemetic. The mechanism of these activities is not known. It is frequently administered in conjunction with a phenothiazine, which reduces the adverse effects of both agents while producing a synergistic antiemetic effect. Adverse effects include euphoria, sedation, dry mouth, and hallucinations.

COMPREHENSION QUESTIONS

31.1 A 56-year-old woman has nausea due to chemotherapy for breast cancer. Droperidol is effective in reducing nausea because it blocks which of the following?

A. ACh receptors in the periphery

B. Dopamine receptors in the CTZ

C. Glucocorticoid receptors in the vomiting center

D. 5-HT₂ receptors in the CTZ

31.2 A patient undergoing chemotherapy with cisplatin has severe nausea. Which of the following would be the drug to use in this patient?

A. Cyclizine

B. Naloxone

C. Ondansetron

D. Scopolamine

31.3 A fisherman uses a transdermal scopolamine patch to assist with the nausea associated with being on a boat. What is the most likely side effect he will experience?

A. Acute dystonic reaction

B. Euphoria

C. Sedation

D. Tremor

ANSWERS

31.1 B. Droperidol is a dopamine-receptor antagonist that diminishes the activity of the CTZ. It is effective in reducing nausea associated with chemotherapy or radiotherapy.

31.2 C. Ondansetron is a serotonin 5-HT₃-receptor antagonist with fewer side effects and greater effectiveness than the other agents in treating patients on chemotherapy.

31.3 C. Sedation is the most common side effect associated with scopolamine patches as a result of stimulation of the muscarinic cholinoreceptor.

REFERENCES

Lohr L. Chemotherapy-induced nausea and vomiting. Cancer J. 2008;14:85–93.

Urba S. Radiation-induced nausea and vomiting. J Natl Compr Canc Netw. 2007;5:60–5.