Granisetron

Nausea and vomiting are common complications of multiple conditions, procedures, and therapies, and adversely affect quality of life in millions of patients each year. Pregnancy-induced nausea alone has been estimated to cause 8.5 million lost working days annually. (1) Postoperative nausea and vomiting have been shown to increase hospitalization costs by $415 per patient. (2) In many instances, therapy for nausea and vomiting is directed at specific, well-studied mechanisms that have been shown to cause nausea.

Mechanism of Action

Treatment of nausea and vomiting ideally involves correcting the underlying cause. When the exact cause is not known or cannot be corrected, symptoms still can be treated.

Three primary pathophysiologic pathways are involved in the stimulation of the physiologic vomiting center in the medulla that directly mediates nausea and vomiting. (3) This center can be stimulated by vestibular fibers, afferent visceral fibers, and input from the chemoreceptor trigger zone in the base of the fourth ventricle (4) (Figure 1). The neurotransmitters histamine, acetylcholine, serotonin, and dopamine frequently are implicated in these pathways and are the targets of most therapeutic modalities.

[FIGURE 1 OMITTED]

Antiemetics

Table 1 lists the primary classes of antiemetics, as well as specific agents in each class. Table 2 lists major adverse effects associated with each class.

ANTIHISTAMINES AND ANTICHOLINERGICS

Antihistamines inhibit the action of histamine at the [H.sub.1] receptor, and anticholinergic agents inhibit the action of acetylcholine at the muscarinic receptor. Both drug classes limit stimulation of the vomiting center from the vestibular system (which is rich in histamine and acetylcholine) but have minimal effect on afferent visceral stimulation. (5)

Antihistamines such as meclizine (Antivert) are associated with minor side effects involving the central nervous system, such as confusion, sedation, dizziness, tinnitus, insomnia, incoordination, fatigue, and tremors. (5,6) Scopolamine (Transderm Scop) is a primary antimuscarinic agent with prominent central nervous system activity. Both antihistamines and anticholinergics can have anticholinergic side effects, including dry mouth, urinary retention, blurred vision, and exacerbation of narrow-angle glaucoma. In general, however, these drugs have few severe adverse effects.

Antihistamine and anticholinergic drugs are relatively inexpensive. Antihistamines cost less than 50 cents per dose, and a scopolamine patch, which provides three days of therapy, costs approximately $5. (7)

DOPAMINE ANTAGONISTS

Dopamine antagonists minimize the effect of dopamine at the [D.sub.2] receptor in the chemoreceptor trigger zone, thereby limiting emetic input to the medullary vomiting center. Although dopamine antagonists are inexpensive and have diffuse efficacy, they have an extensive side effect profile that includes sedation, orthostatic hypotension, and extrapyramidal symptoms such as tardive dyskinesia. (6,8) Consequently, serotonin antagonists have replaced dopamine antagonists for many indications.

Rare reactions to dopamine antagonists include neuroleptic malignant syndrome and blood dyscrasias. Because droperidol (Inapsine) has been associated with QT prolongation, 12-lead electrocardiography is recommended before treatment is initiated. Droperidol carries a "black-box" warning about the risk of sudden cardiac death; consequently, some pharmacies no longer stock the drug. However, various experts (9,10) argue that the warning about droperidol is based on case reports, and that randomized controlled trials (RCTs) have found droperidol to be safe and cost-effective when given in antiemetic dosages.

Dopamine antagonists are relatively inexpensive, typically costing approximately $1 per dose. Rectal and parenteral doses cost three to five times more than oral doses. (7)

SEROTONIN ANTAGONISTS

Selective serotonin antagonists inhibit the action of serotonin at the 5-[hydroxytryptamine.sub.3] (5-H[T.sub.3]) receptor in the small bowel, vagus nerve, and chemoreceptor trigger zone. This action subsequently decreases afferent visceral and chemoreceptor trigger zone stimulation of the medullary vomiting center. Because of their diffuse blockade of serotonin, these agents have become the primary treatment for a variety of causes of nausea.

In general, the serotonin antagonists have been shown to be safe, with minimal significant side effects. Headache, diarrhea, and fatigue (the most common side effects) occur independently of dosage and route of administration. (11,12) Hypersensitivity reactions to these agents occur rarely but have been associated with complications ranging from urticaria to bronchospasm and anaphylaxis. Transient elevation of liver enzyme levels occurs in a small number of patients treated with serotonin antagonists.

In clinical trials, serotonin antagonists have caused self-limited, asymptomatic QT prolongation and QRS widening. (13) Therefore, these agents should be used with caution in patients with underlying QT prolongation.

The 5-H[T.sub.3] antagonists are the newest and most expensive antiemetics. The three primary agents--ondansetron (Zofran), dolasetron (Anzemet), and granisetron (Kytril)--have similar efficacy. Costs for these agents in the treatment of patients with postoperative nausea range from approximately $17 to $195 per dose. (7)

Clinical Situations

NAUSEA INDUCED BY VESTIBULAR OR CENTRAL NERVOUS SYSTEM CAUSES

Antiemetics frequently are used to treat nausea induced by vestibular or central nervous system causes. Unlike other forms of nausea, which tend to be mediated by dopamine and serotonin, vestibular system-induced nausea is mediated primarily by histamine and acetylcholine (Table 3). Consequently, the American Gastroenterological Association (AGA) recommends the use of antihistamines and anticholinergics in the treatment of nausea secondary to vertigo and motion sickness. (14)

Migraine headaches frequently are associated with nausea. Although the mechanism is not well understood, antiemetics are useful in the treatment of nausea, and of the headache itself. Because of the efficacy of dopamine antagonists in treating migraine headaches, dopamine is thought to be a primary mediator. A small RCT (15) involving 29 patients found that intramuscular droperidol and meperidine (Demerol) provided equal pain relief.

Evidence-based guidelines (16) developed by a committee from the American Academy of Family Physicians, the American Academy of Neurology, and other organizations support the use of intravenous metoclopramide (Reglan) and intravenous, intramuscular, and rectal prochlorperazine (Compazine) as singleagent therapies in patients with acute migraine headaches and nausea. The committee concluded that oral antiemetics and 5-H[T.sub.3] antagonists are appropriate for adjunctive treatment of migraine-associated nausea.

PREGNANCY-INDUCED NAUSEA

Between 70 and 85 percent of women have nausea during pregnancy, and an estimated 0.5 percent develop hyperemesis gravidarum. 17 The pathogenesis of nausea in pregnancy is not completely understood but is thought to be multifactorial. Several antiemetic drug classes have been shown to be effective treatments.

A recent Cochrane review found that antiemetics generally are effective in treating pregnancy-induced nausea, but that little information exists about fetal outcomes. (17) Consequently, many physicians avoid using antiemetics until patients have dehydration, weight loss, or electrolyte abnormalities. When these criteria are met, treatment with promethazine (Phenergan) usually is initiated.

One small RCT (18) in patients hospitalized because of hyperemesis gravidarum found that promethazine is as effective as ondansetron and is more cost-effective. Another small study (19) showed that oral methylprednisolone (Medrol) is superior to promethazine in the treatment of hyperemesis gravidarum and can replace or augment other agents in refractory cases.

Complementary and alternative therapies have become popular in the treatment of pregnancy-induced nausea. Pyridoxine (vitamin B6) has been shown to be safe and effective in dosages of 50 to 200 mg per day. (17,20) One RCT (21) found that oral ginger (1 g per day) is more effective than placebo in controlling nausea and vomiting in early pregnancy; use of ginger generally is thought to be safe. (20) Current evidence on the efficacy of acupressure and acupuncture in treating pregnancy-induced nausea is inconclusive. (17)

INTESTINAL IRRITATION

Intestinal irritation is a frequent cause of nausea. Agents such as Norwalk virus, rotavirus, and Salmonella species cause 1.2 intestinal infections per person per year. (14) Medications such as aspirin and ferrous sulfate can cause nausea through visceral stimulation. Because visceral fibers are mediated primarily by serotonin, 5-H[T.sub.3] antagonists are effective in the treatment of these disorders. (14) Anecdotal reports also indicate significant success for treatment with dopamine antagonists, which may be more cost-effective first-line agents than serotonin antagonists.

Treatment of nausea in children with gastroenteritis remains controversial. In a 1996 position statement, (22) the American Academy of Pediatrics recommended that the use of antiemetics be avoided in children because of potential side effects and questionable benefit. However, many family physicians now use 5-H[T.sub.3] antagonists in dehydrated children. RCTs have shown that oral and intravenous ondansetron therapy is safe in children and reduces hospital admission rates. (23,24)

POSTOPERATIVE NAUSEA AND VOMITING

Nausea affects an estimated 30 percent of patients within 24 hours after surgery. (25) The nausea is mediated primarily by two pathophysiologic pathways. First, intestinal irritation and postoperative stasis stimulate the vomiting center via visceral fibers rich in serotonin. Second, general anesthetics directly activate the chemoreceptor trigger zone which, in turn, stimulates the vomiting center via dopamine and serotonin.

Traditionally, dopamine antagonists such as droperidol and promethazine have been used to treat patients with postoperative nausea and vomiting. Metoclopramide, another dopamine antagonist with prokinetic activity, commonly is used in patients with nausea caused by intestinal stasis. In general, low-dosage droperidol therapy is safe and effective for preventing postoperative nausea and vomiting, and is more cost-effective than treatment with 5-H[T.sub.3] antagonists. (10,26) However, serotonin antagonists also minimize postoperative nausea, and the AGA recommends using them as first-line agents for preventing and treating postoperative nausea and vomiting. (14)

Dexamethasone has been shown to be a useful adjunct to serotonin antagonists in the prevention and treatment of postoperative nausea and vomiting. (27)

A reasonable approach to preventing and treating postoperative nausea and vomiting begins with the identification of risk factors, which include female sex, history of postoperative nausea and vomiting, nonsmoking status, perioperative opioid use, general anesthesia, and abdominal, gynecologic, or ear, nose, and throat procedures.

If a patient is at low risk for postoperative nausea and vomiting, prophylaxis is not required, and serotonin antagonists can be used as rescue medications after surgery. In the moderate-risk patient, droperidol should be used for prophylaxis and serotonin antagonists for rescue medications if breakthrough nausea occurs. In a patient at high risk for nausea and vomiting after surgery, droperidol and dexamethasone should be used for prophylaxis, and serotonin antagonists should be given to treat breakthrough nausea. (28)

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

REFERENCES

(1.) Gadsby R. Pregnancy sickness and symptoms: your questions answered. Prof Care Mother Child 1994;4:16-7.

(2.) Gadsby R, Barnie-Adshead AM, Jagger C. A prospective study of nausea and vomiting during pregnancy [published erratum appears in Br J Gen Pract 1993;43:325]. Br J Gen Pract 1993;43:245-8.

(3.) Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001;111(suppl 8A):106S-12S.

(4.) McQuaid KR. Alimentary tract. In: Tierney LM, ed. Current medical diagnosis and treatment, 2003. 42d ed. New York: Lange Medical Books/McGraw-Hill, 2003:573-5.

(5.) Pasricha PJ. Prokinetic agents, antiemetics, and agents used in irritable bowel syndrome. In: Goodman LS, Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman's The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001:1021-36.

(6.) Babe KS Jr, Serafin WE. Histamine, bradykinin, and their antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman AG, eds. Goodman and Gilman's The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001:587-91.

(7.) 2003 drug topics red book. Montvale, N.J.: Medical Economics, 2003.

(8.) Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman AG, eds. Goodman and Gilman's The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:414-7.

(9.) Gan TJ, White PF, Scuderi PE, Watcha MF, Kovac A. FDA "black box" warning regarding use of droperidol for postoperative nausea and vomiting: is it justified? [Letter] Anesthesiology 2002;97:287.

(10.) Henzi I, Sonderegger J, Tramer MR. Efficacy, dose-response, and adverse effects of droperidol for prevention of postoperative nausea and vomiting. Can J Anaesth 2000;47:537-51.

(11.) ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999;56:729-64.

(12.) Drug facts and comparisons 2003. 57th ed. St. Louis: Facts and Comparisons, 2003.

(13.) De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf 2002;25:263-86.

(14.) Quigley EM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology 2001;120:263-86.

(15.) Richman PB, Allegra J, Eskin B, Doran J, Reischel U, Kaiafas C, et al. A randomized clinical trial to assess the efficacy of intramuscular droperidol for the treatment of acute migraine headache. Am J Emerg Med 2002;20:39-42.

(16.) Matchar DB, Young WB, Rosenberg JH, Pietrzak MP, Silberstein SD, Lipton RB, et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. Accessed December 12, 2003, at: www.aan.com/professionals/practice/pdfs/gl0087. pdf.

(17.) Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev 2003(4):CD000145.

(18.) Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison JC. A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996;175:1565-8.

(19.) Safari HR, Fassett MJ, Souter IC, Alsulyman OM, Goodwin TM. The efficacy of methylprednisolone in the treatment of hyperemesis gravidarum: a randomized, double-blind, controlled study. Am J Obstet Gynecol 1998;179:921-4.

(20.) University of Texas at Austin, School of Nursing, Family Nurse Practitioner Program. Evaluation and management of nausea and vomiting in early pregnancy (less than or equal to 20 weeks gestation). Austin, Texas: University of Texas at Austin, School of Nursing, 2002. Accessed January 22, 2004, at: http://www.guideline.gov/summary/summary.aspx ?doc_id=3228.

(21.) Vutyavanich T, Kraisarin T, Ruangsri R. Ginger for nausea and vomiting in pregnancy: randomized, double-masked, placebo-controlled trial. Obstet Gynecol 2001;97:577-82.

(22.) Practice parameter: the management of acute gastroenteritis in young children. American Academy of Pediatrics, Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. Pediatrics 1996;97:424-35.

(23.) Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D. A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med 2002;39:397-403.

(24.) Reeves JJ, Shannon MW, Fleisher GR. Ondansetron decreases vomiting associated with acute gastroenteritis: a randomized, controlled trial. Pediatrics 2002;109:e62.

(25.) Tramer MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part I. Efficacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand 2001;45:4-13.

(26.) Watcha MF, Smith I. Cost-effectiveness analysis of antiemetic therapy for ambulatory surgery. J Clin Anesth 1994;6:370-7.

(27.) Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2000;90:186-94.

(28.) Watcha MF. Postoperative nausea and emesis. Anesthesiol Clin North Am 2002;20:709-22.

ZACHARY A. FLAKE, M.D., is a resident in the Fort Collins (Colo.) Family Medicine Residency Program. Dr. Flake received his medical degree from the University of Kansas School of Medicine, Kansas City, Kan.

ROBERT D. SCALLEY, PHARM.D., is professor of pharmacy at the University of Wyoming School of Pharmacy, Laramie. Dr. Scalley earned his pharmacy degree from the University of Southern California School of Pharmacy, Los Angeles.

AUSTIN G. BAILEY, M.D., is program director of the Fort Collins Family Medicine Residency Program and associate clinical professor of family medicine at the University of Colorado School of Medicine, Denver. He earned his medical degree and completed a residency in family medicine at Texas Tech University Health Sciences Center School of Medicine, Lubbock. Dr. Bailey also completed a fellowship in faculty development at the McLennan County Medical Education and Research Foundation Program, Waco, Texas.

Address correspondence to Zachary A. Flake, M.D., Fort Collins Family Medicine Residency Program, 1025 Pennock Place, Fort Collins, CO 80524 (e-mail: flakza@pvhs.org). Reprints are not available from the authors.

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