PHARMACOLOGY FACTS
Antiemetics: Focus on Pharmacology Julie Golembiewski, PharmD THE ACT OF VOMITING is controlled by the vomiting center, located in the medulla oblongata in close proximity to the nucleus of the solitary tract in the brainstem. The vomiting reflex can be activated by one or more sources: 1) the chemoreceptor trigger zone (CTZ), 2) the vestibular system (via cranial nerve VIII), 3) vagal and spinal afferent nerves from the gastrointestinal (GI) tract, and 4) the central nervous system (eg, stress, anticipatory nausea/vomiting before chemotherapy). The area postrema/CTZ/nucleus of the solitary tract is rich in many ‘‘emetogenic’’ receptors: serotonin type-3 (5-HT3), histamine type-1 (H1), muscarinic cholinergic type-1 (M1), dopamine type-2 (D2), neurokinin type-1 (NK1), and opioid receptors. Stimulation of M1 and H1 receptors in the vestibular system, via the CTZ, also activate the vomiting center. Vagal and afferent nerves from the GI tract are rich in 5-HT3 receptors, that when stimulated, can also trigger the vomiting reflex.1-4
Patient Risk Factors Female sex, history of postoperative nausea and vomiting (PONV), non-smoking status, and use of postoperative opioids predict an adult patient’s risk for PONV, with the risk increasing from 10% when no factors are present to 80% when four factors are present.5 Female sex, history of PONV, age , 50 years, use of opioids in the postanesthesia care unit (PACU), and nausea in PACU predict an adult patient’s risk for postdischarge nausea and vomiting (PDNV), with the risk increasing from 10% when no factors are present to 80%
Julie Golembiewski, PharmD, is a Clinical Associate Professor, Departments of Pharmacy Practice and Anesthesiology, University of Illinois at Chicago, Chicago, IL. Conflict of interest: None to report. Address correspondence to Julie Golembiewski, University of Illinois Hospital & Health Sciences System, 1740 West Taylor Street, Suite 3200, MC 515, Chicago, IL 60612; e-mail address: [email protected]. Ó 2014 by American Society of PeriAnesthesia Nurses 1089-9472/$36.00 http://dx.doi.org/10.1016/j.jopan.2014.09.001
514
when five factors are present.6 The continued use of opioids for postoperative analgesia, as well as tissue trauma and inflammation from the surgery itself (altering GI motility and producing inflammation), have also been postulated to contribute to PDNV.2
Antiemetics The neuronal mechanisms and emetogenic receptors involved in triggering PONV provide the rationale for administration of one or more antiemetics to prevent PONV in a patient at moderate or high risk. Antiemetic drugs that work by different mechanisms of action have additive effects, with the addition of each antiemetic reducing relative risk by approximately 25%. The absolute PONV risk, however, is reduced less and less with each additional drug and never reaches zero.2 This explains why the administration of more than two prophylactic antiemetics is generally reserved for high risk patients7 (Table 1). Droperidol, haloperidol, and prochlorperazine are D2 receptor antagonists, binding to D2 receptors in the area postrema. Low dose droperidol (0.625 to 1.25 mg intravenous [IV]) can be administered to prevent or treat PONV, with comparable efficacy to ondansetron or dexamethasone when given for prophylaxis.8 Low dose haloperidol (1 to 2 mg IV) prevents PONV, with comparable efficacy to ondansetron or droperidol.9 Prochlorperazine (5 to 10 mg IV or IM) is generally reserved for treatment of PONV. In these doses, adverse effects include extrapyramidal symptoms (EPS) such as restlessness as well as drowsiness (prochlorperazine). Droperidol and haloperidol, particularly at higher doses, are associated with a higher risk of QT prolongation and torsades de pointes.10,11 The use of droperidol as a first-line prophylactic antiemetic declined significantly following the FDA black box warning in 2001 about serious proarrythmic effects. Recent literature, however, provides an evidence-based approach for the safe use of droperidol for prevention or treatment of PONV in a patient under anesthesia care.12
Journal of PeriAnesthesia Nursing, Vol 29, No 6 (December), 2014: pp 514-518
Unknown
Dopamine type 2 receptor antagonist
Serotonin type 3 receptor antagonism (centrally and peripherally in gut)
Dopamine type 2 receptor antagonist
Dopamine type 2 receptor antagonist, enhances upper GI motility and gastric emptying Serotonin type 3 receptor antagonist (centrally and peripherally in gut)
Serotonin type 3 receptor antagonist (centrally and peripherally in gut) Histamine type 1 and muscarinic type 1 receptor antagonist
Dexamethasone21-23,29
Droperidol10,12,29
Granisetron16,17,29
Haloperidol9,11,29
Metoclopramide13,14,29
Palonosetron18,19,29
Promethazine25,26,29
Ondansetron7,20,29
Substance P/neurokinin 1 receptor antagonist
Mechanism of Action/Class
Aprepitant27-29
Drug
6.25 to 25 mg IM or IV
0.075 mg IV
4 mg IV
10 mg IV
1 mg IV or IM
0.35 to 1 mg IV
0.625 to 1 mg IV
4 mg IV
40 mg orally within 3 h before induction
Typical Adult Dose
Headache, constipation, QT prolongation Drowsiness, dry mouth, blurred vision, confusion, urinary retention
Sedation, dizziness, EPS (eg, inner restlessness, inability to sit still, movement disorder) Headache, constipation, QT prolongation
EPS (eg, restlessness, inability to sit still, movement disorder), QT prolongation
Headache, constipation, QT prolongation
Restlessness and other EPS (eg, movement disorder), QT prolongation, ventricular arrythmias
Perianal pruritus, elevated blood glucose
Fatigue, weakness, headache, constipation
Adverse Effects
Table 1. Antiemetics for Prevention and Treatment of PONV in Adults
(Continued )
8 mg ODT as effective as 4 mg IV; other drugs may contribute to QT prolongation Second generation; long duration of action Reserve for treatment of PONV; inadvertent perivascular or intraarticular administration can cause severe tissue injury; IM route preferred; if IV route used, ensure IV is properly functioning,
Long (48 h) duration of action; role in routine prophylaxis not established Not appropriate for diabetic patients with widely fluctuating blood glucose Avoid in patients with prolonged QT interval or significantly reduced ventricular systolic function; other drugs may contribute to QT prolongation Used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders; other drugs may contribute to QT prolongation Antiemetic efficacy similar to droperidol; avoid in patients with prolonged QT interval or significantly reduced ventricular systolic function; other drugs may contribute to QT prolongation Administer slow IV push
Comments
PHARMACOLOGY FACTS 515
JULIE GOLEMBIEWSKI PONV, postoperative nausea and vomiting; IV, intravenous; EPS, extrapyramidal symptoms; IM, intramuscular; CNS, central nervous system; ODT, ondansetron disintegrating tablet.
1 Patch Muscarinic type 1 receptor antagonist Scopolamine24,29
Visual disturbances, dry mouth, dizziness, drowsiness
5 to 10 mg IV or IM Dopamine type 2 receptor antagonist
Drowsiness, EPS (eg, inner restlessness, inability to sit still, movement disorder)
dilute, and administer slowly; sedation additive with other CNS depressants (eg, opioid) Reserve for treatment of PONV; IM route preferred; if IV route used, give slowly (#5 mg/min); sedation additive with other CNS depressants (eg, opioid) Prophylaxis only; 2 to 4 h onset; wash hands after handling patch and avoid touching eyes Prochlorperazine29
Typical Adult Dose Mechanism of Action/Class Drug
Table 1. Continued
Adverse Effects
Comments
516
Metoclopramide, a D2 receptor antagonist, is primarily used for its gastric prokinetic effect. A systematic review found that metoclopramide was not effective in reducing PONV.13 However, when the report of research fraud by Fujii emerged, De Oliveira et al14 reanalyzed the studies without Fujii’s research and found that metoclopramide 10 mg IV does effectively prevent PONV. However, it was noted that it more effectively prevented vomiting (number needed to treat [NNT] 5 5.9) than nausea (NNT 5 10.5). Metoclopramide 10 mg IV effectively prevents PONV associated with Caesarean delivery.15 Adverse effects of metoclopramide include sedation, dizziness, and EPS (eg, restlessness).13 Ondansetron, granisetron, and palonosetron are 5HT3 receptor antagonists, acting centrally in the area postrema as well as peripherally in the GI tract. Ondansetron is the most commonly used antiemetic for prevention and treatment of PONV, with comparable efficacy to droperidol or dexamethasone for prophylaxis.8 Granisetron, in low doses (0.1 mg IV), has comparable efficacy to ondansetron.16,17 Palonsetron is a second generation 5-HT3 antagonist that interacts with sites distinct from where the first generation agents bind, and it has a long half-life (40 hours). Although the comparative efficacy of palonsetron is evolving, it is possible that palonsetron is more effective than ondansetron18 with an antiemetic effect of up to 72 hours.19 Adverse effects of serotonin antagonists include headache, constipation, and QT prolongation, particularly in higher doses.20 Dolastron is no longer marketed in the United States. Dexamethasone is an effective antiemetic, although its exact antiemetic mechanism of action is not clear. Dexamethasone 4 mg IV is as effective as droperidol or ondansetron for preventing PONV.8 Although a meta-analysis21 found that a prophylactic dose of .0.1 mg/kg (8 to 10 mg IV) reduces postoperative pain and opioid consumption, the effect is small and may not be clinically significant.22 Adverse effects of dexamethasone include perianal pruritus and elevated blood glucose, which can persist for up to 24 hours22 and more pronounced in patients with higher body mass index and higher baseline HBA1c.23 A single pre- or intraoperative antiemetic dose of dexamethasone has not been shown to increase
PHARMACOLOGY FACTS
517
the risk of infection or delay postoperative wound healing.22 Transdermal scopolamine is a M1 receptor antagonist (anticholinergic agent) that effectively reduces PONV when the patch is applied either the day/ evening before surgery or on the day of surgery.24 The patch should not be used in children and should be used with caution in elderly patients or patients with impaired liver or kidney function. In these patients, the dose delivered by the patch is more likely to produce excessive central nervous system effects such as confusion, ataxia, disorientation, restlessness, sedation, and, possibly, acute toxic psychosis. Common adverse effects of transdermal scopolamine include visual disturbances and dry mouth.24 Promethazine is a H1 and M1 receptor antagonist generally reserved for treatment of PONV. For patients who received ondansetron prophylaxis, promethazine 6.25 mg is significantly more effective than ondansetron for treating PONV. Increasing the dose of promethazine does not improve efficacy.25 Adverse effects of promethazine include drowsiness, dry mouth, blurred vision, confusion, and urinary retention. Unintentional intraarterial administration or extravasation of promethazine can cause severe tissue injury. The preferred route of administration is deep IM. If IV administration is used, promethazine should
be diluted (maximum concentration: 25 mg/mL) and administered slowly (maximum rate: 25 mg/ min) through a properly functioning IV.26 Aprepitant is an oral NK-1 receptor antagonist with a long (40 hours) half-life. Aprepitant has been shown to have comparable antiemetic efficacy to ondansetron,27,28 with a more pronounced effect on vomiting than nausea.28 Because clinical experience with aprepitant is limited, its role in routine prophylaxis is not clear.7 Adverse effects of aprepitant include headache, fatigue, weakness, and constipation.
Conclusion There are many stimuli that contribute to PONV and PDNV. Stimulation of one or more of the ‘‘emetogenic receptors’’ (5-HT3, H1, M1, D2, NK1 receptors) can activate the vomiting center. Prophylactic administration of two or more antiemetics that work by a different mode of action (eg, block different emetogenic receptors) is recommended for patients at moderate-to-high risk for PONV. If PONV occurs within 6 hours postoperatively, treatment with an antiemetic that works by a different mode of action is more effective than a repeat dose of the prophylactic antiemetic. If PONV occurs more than 6 hours postoperatively, the emetic episode may be treated with one of the antiemetics administered for prophylaxis.
References 1. Gan TJ. Management of Postoperative Nausea and Vomiting. The ASA Refresher Courses in Anesthesiology CME Program, Chapter 6, Volume 37. The American Society of Anesthesiologists, Inc: 2009; 69-80. 2009;. Available at: www.asa-refresher.com. Accessed September 3, 2014. 2. Horn CC, Wallisch WJ, Homanics GE, Williams JP. Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting. Eur J Pharmacol. 2014;722:55-66. 3. Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol. 2014;722:67-78. 4. McQuaid KR. Drugs used in the treatment of gastrointestinal disease. In: Katzung BG, Masters SB, Trevor PJ, eds. Basic & Clinical Pharmacology, Chapter 62, 12th ed. The McGrawHill Companies Inc; 2012. 5. Apfel CC, L€a€ar€a E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: Conclusions from cross-validations between two centers. Anesthesiology. 1999;91:693-700. 6. Apfel CC, Philip BK, Cakmakkays OS, et al. Who is at risk for postdischarge nausea and vomiting after ambulatory surgery? Anesthesiology. 2012;117:475-486.
7. Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014;118:85-113. 8. Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441-2451. 9. Chaparro C, Moreno D, Ramirez V, et al. Haloperidol as prophylactic treatment for postoperative nausea and vomiting: Systematic literature review. Rev Colomb Anestesiol. 2013;41:34-43. 10. Inapsine (droperidol) Dear Healthcare Professional Letter. 2001. Available at: http://www.fda.gov/safety/medwatch/ safetyinformation/safetyalertsforhumanmedicalproducts/ucm 173778.htm. Accessed September 3, 2014. 11. FDA Alert. Information for Healthcare Professionals: Haloperidol (marketed as Haldol, Haldol Decanoate and Haldol Lactate). 2007. Available at: http://www.fda.gov/drugs/drugsafety/ postmarketdrugsafetyinformationforpatientsandproviders/drugsafety informationforheathcareprofessionals/ucm085203.htm. Accessed September 3, 2014. 12. Moore J. The Use of Droperidol in Anesthesia Care. California Society of Anesthesiologists Bulletin; 2009:28-34. 2009.
518
Available at: http://www.csahq.org/pdf/bulletin/droperidol_ 58_1.pdf. Accessed September 3, 2014. 13. Henzi I, Walder B, Tramer M. Metoclopramide in the prevention of postoperative nausea and vomiting: A quantitative systematic review of randomized, placebo-controlled studies. Br J Anaesth. 1999;83:761-771. 14. De Oliveira GS Jr., Castro-Alves LJ, Chang R, et al. Systemic metoclopramide to prevent postoperative nausea and vomiting: A meta-analysis without Fujii’s studies. Br J Anaesth. 2012;109:688-697. 15. Mishriky BM, Habib AS. Metoclopramide for nausea and vomiting prophylaxis during and after Caesarean delivery: A systematic review and meta-analysis. Br J Anaesth. 2012;108: 374-383. 16. Erhan Y, Erhan E, Aydede H, et al. Ondansetron, granisetron, and dexamethasone compared for the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: A randomized placebo-controlled study. Surg Endosc. 2008;22:14871492. 17. Bridges JD, Nettle CB, Dugirrala VJ, et al. Low-dose granisetron for the prevention of postoperative nausea and vomiting. J Appl Res. 2006;6:223-229. 18. Bajwa SS, Bajwa SK, Kaur J, et al. Palonsetron: A novel approach to control postoperative nausea and vomiting in day case surgery. Saudi J Anaesth. 2011;5:19-24. 19. Kovac AL, Eberhart L, Kotarski J, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonsetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg. 2008;107:439-444. 20. FDA Drug Safety Communication. New information regarding QT prolongation with ondansetron (Zofran). Available at: http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Accessed September 3, 2014.
JULIE GOLEMBIEWSKI 21. De Oliveira GS, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain. Anesthesiology. 2011;115:575-588. 22. Weldron NH, Jones CA, Gan TJ, et al. Impact of perioperative dexamethasone on postoperative analgesia and sideeffects: Systematic review and meta-analysis. Br J Anaesth. 2013;110:191-200. 23. Hans P, Vanthuyne A, Dewandre PY, et al. Blood glucose concentration profile after 10 mg dexamethasone in nondiabetic and type 2 diabetic patients undergoing abdominal surgery. Br J Anaesth. 2006;97:164-170. 24. Apfel CC, Zhang K, George E, et al. Transdermal scopolamine for the prevention of postoperative nausea and vomiting: A systematic review and meta-analysis. Clin Ther. 2010;32: 1987-2002. 25. Habib AS, Reuveni J, Taguchi A, et al. A comparison of ondansetron with promethazine for treating postoperative nausea and vomiting in patients who received prophylaxis with ondansetron: A retrospective database analysis. Anesth Analg. 2007; 1004:548-551. 26. FDA Requires Boxed Warning for Promethazine Hydrochloride Injection. 2009. Available at: http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm182498.htm. Accessed September 4, 2014. 27. Diemunsch P, Gan TJ, Philip BK, et al. Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: A randomized, double-blind phase III trial in patients undergoing open abdominal surgery. Br J Anaesth. 2007;99:202-211. 28. Gan TJ, Apfel CC, Kovac A, et al. A randomized, doubleblind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg. 2007;104:1082-1089. 29. Drug Information Handbook, 23rd ed. Hudson, OH: LexicompÒ; 2014-2015.
Antiemetics: Focus on Pharmacology Julie Golembiewski, PharmD THE ACT OF VOMITING is controlled by the vomiting center, located in the medulla oblongata in close proximity to the nucleus of the solitary tract in the brainstem. The vomiting reflex can be activated by one or more sources: 1) the chemoreceptor trigger zone (CTZ), 2) the vestibular system (via cranial nerve VIII), 3) vagal and spinal afferent nerves from the gastrointestinal (GI) tract, and 4) the central nervous system (eg, stress, anticipatory nausea/vomiting before chemotherapy). The area postrema/CTZ/nucleus of the solitary tract is rich in many ‘‘emetogenic’’ receptors: serotonin type-3 (5-HT3), histamine type-1 (H1), muscarinic cholinergic type-1 (M1), dopamine type-2 (D2), neurokinin type-1 (NK1), and opioid receptors. Stimulation of M1 and H1 receptors in the vestibular system, via the CTZ, also activate the vomiting center. Vagal and afferent nerves from the GI tract are rich in 5-HT3 receptors, that when stimulated, can also trigger the vomiting reflex.1-4
Patient Risk Factors Female sex, history of postoperative nausea and vomiting (PONV), non-smoking status, and use of postoperative opioids predict an adult patient’s risk for PONV, with the risk increasing from 10% when no factors are present to 80% when four factors are present.5 Female sex, history of PONV, age , 50 years, use of opioids in the postanesthesia care unit (PACU), and nausea in PACU predict an adult patient’s risk for postdischarge nausea and vomiting (PDNV), with the risk increasing from 10% when no factors are present to 80%
Julie Golembiewski, PharmD, is a Clinical Associate Professor, Departments of Pharmacy Practice and Anesthesiology, University of Illinois at Chicago, Chicago, IL. Conflict of interest: None to report. Address correspondence to Julie Golembiewski, University of Illinois Hospital & Health Sciences System, 1740 West Taylor Street, Suite 3200, MC 515, Chicago, IL 60612; e-mail address: [email protected]. Ó 2014 by American Society of PeriAnesthesia Nurses 1089-9472/$36.00 http://dx.doi.org/10.1016/j.jopan.2014.09.001
514
when five factors are present.6 The continued use of opioids for postoperative analgesia, as well as tissue trauma and inflammation from the surgery itself (altering GI motility and producing inflammation), have also been postulated to contribute to PDNV.2
Antiemetics The neuronal mechanisms and emetogenic receptors involved in triggering PONV provide the rationale for administration of one or more antiemetics to prevent PONV in a patient at moderate or high risk. Antiemetic drugs that work by different mechanisms of action have additive effects, with the addition of each antiemetic reducing relative risk by approximately 25%. The absolute PONV risk, however, is reduced less and less with each additional drug and never reaches zero.2 This explains why the administration of more than two prophylactic antiemetics is generally reserved for high risk patients7 (Table 1). Droperidol, haloperidol, and prochlorperazine are D2 receptor antagonists, binding to D2 receptors in the area postrema. Low dose droperidol (0.625 to 1.25 mg intravenous [IV]) can be administered to prevent or treat PONV, with comparable efficacy to ondansetron or dexamethasone when given for prophylaxis.8 Low dose haloperidol (1 to 2 mg IV) prevents PONV, with comparable efficacy to ondansetron or droperidol.9 Prochlorperazine (5 to 10 mg IV or IM) is generally reserved for treatment of PONV. In these doses, adverse effects include extrapyramidal symptoms (EPS) such as restlessness as well as drowsiness (prochlorperazine). Droperidol and haloperidol, particularly at higher doses, are associated with a higher risk of QT prolongation and torsades de pointes.10,11 The use of droperidol as a first-line prophylactic antiemetic declined significantly following the FDA black box warning in 2001 about serious proarrythmic effects. Recent literature, however, provides an evidence-based approach for the safe use of droperidol for prevention or treatment of PONV in a patient under anesthesia care.12
Journal of PeriAnesthesia Nursing, Vol 29, No 6 (December), 2014: pp 514-518
Unknown
Dopamine type 2 receptor antagonist
Serotonin type 3 receptor antagonism (centrally and peripherally in gut)
Dopamine type 2 receptor antagonist
Dopamine type 2 receptor antagonist, enhances upper GI motility and gastric emptying Serotonin type 3 receptor antagonist (centrally and peripherally in gut)
Serotonin type 3 receptor antagonist (centrally and peripherally in gut) Histamine type 1 and muscarinic type 1 receptor antagonist
Dexamethasone21-23,29
Droperidol10,12,29
Granisetron16,17,29
Haloperidol9,11,29
Metoclopramide13,14,29
Palonosetron18,19,29
Promethazine25,26,29
Ondansetron7,20,29
Substance P/neurokinin 1 receptor antagonist
Mechanism of Action/Class
Aprepitant27-29
Drug
6.25 to 25 mg IM or IV
0.075 mg IV
4 mg IV
10 mg IV
1 mg IV or IM
0.35 to 1 mg IV
0.625 to 1 mg IV
4 mg IV
40 mg orally within 3 h before induction
Typical Adult Dose
Headache, constipation, QT prolongation Drowsiness, dry mouth, blurred vision, confusion, urinary retention
Sedation, dizziness, EPS (eg, inner restlessness, inability to sit still, movement disorder) Headache, constipation, QT prolongation
EPS (eg, restlessness, inability to sit still, movement disorder), QT prolongation
Headache, constipation, QT prolongation
Restlessness and other EPS (eg, movement disorder), QT prolongation, ventricular arrythmias
Perianal pruritus, elevated blood glucose
Fatigue, weakness, headache, constipation
Adverse Effects
Table 1. Antiemetics for Prevention and Treatment of PONV in Adults
(Continued )
8 mg ODT as effective as 4 mg IV; other drugs may contribute to QT prolongation Second generation; long duration of action Reserve for treatment of PONV; inadvertent perivascular or intraarticular administration can cause severe tissue injury; IM route preferred; if IV route used, ensure IV is properly functioning,
Long (48 h) duration of action; role in routine prophylaxis not established Not appropriate for diabetic patients with widely fluctuating blood glucose Avoid in patients with prolonged QT interval or significantly reduced ventricular systolic function; other drugs may contribute to QT prolongation Used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders; other drugs may contribute to QT prolongation Antiemetic efficacy similar to droperidol; avoid in patients with prolonged QT interval or significantly reduced ventricular systolic function; other drugs may contribute to QT prolongation Administer slow IV push
Comments
PHARMACOLOGY FACTS 515
JULIE GOLEMBIEWSKI PONV, postoperative nausea and vomiting; IV, intravenous; EPS, extrapyramidal symptoms; IM, intramuscular; CNS, central nervous system; ODT, ondansetron disintegrating tablet.
1 Patch Muscarinic type 1 receptor antagonist Scopolamine24,29
Visual disturbances, dry mouth, dizziness, drowsiness
5 to 10 mg IV or IM Dopamine type 2 receptor antagonist
Drowsiness, EPS (eg, inner restlessness, inability to sit still, movement disorder)
dilute, and administer slowly; sedation additive with other CNS depressants (eg, opioid) Reserve for treatment of PONV; IM route preferred; if IV route used, give slowly (#5 mg/min); sedation additive with other CNS depressants (eg, opioid) Prophylaxis only; 2 to 4 h onset; wash hands after handling patch and avoid touching eyes Prochlorperazine29
Typical Adult Dose Mechanism of Action/Class Drug
Table 1. Continued
Adverse Effects
Comments
516
Metoclopramide, a D2 receptor antagonist, is primarily used for its gastric prokinetic effect. A systematic review found that metoclopramide was not effective in reducing PONV.13 However, when the report of research fraud by Fujii emerged, De Oliveira et al14 reanalyzed the studies without Fujii’s research and found that metoclopramide 10 mg IV does effectively prevent PONV. However, it was noted that it more effectively prevented vomiting (number needed to treat [NNT] 5 5.9) than nausea (NNT 5 10.5). Metoclopramide 10 mg IV effectively prevents PONV associated with Caesarean delivery.15 Adverse effects of metoclopramide include sedation, dizziness, and EPS (eg, restlessness).13 Ondansetron, granisetron, and palonosetron are 5HT3 receptor antagonists, acting centrally in the area postrema as well as peripherally in the GI tract. Ondansetron is the most commonly used antiemetic for prevention and treatment of PONV, with comparable efficacy to droperidol or dexamethasone for prophylaxis.8 Granisetron, in low doses (0.1 mg IV), has comparable efficacy to ondansetron.16,17 Palonsetron is a second generation 5-HT3 antagonist that interacts with sites distinct from where the first generation agents bind, and it has a long half-life (40 hours). Although the comparative efficacy of palonsetron is evolving, it is possible that palonsetron is more effective than ondansetron18 with an antiemetic effect of up to 72 hours.19 Adverse effects of serotonin antagonists include headache, constipation, and QT prolongation, particularly in higher doses.20 Dolastron is no longer marketed in the United States. Dexamethasone is an effective antiemetic, although its exact antiemetic mechanism of action is not clear. Dexamethasone 4 mg IV is as effective as droperidol or ondansetron for preventing PONV.8 Although a meta-analysis21 found that a prophylactic dose of .0.1 mg/kg (8 to 10 mg IV) reduces postoperative pain and opioid consumption, the effect is small and may not be clinically significant.22 Adverse effects of dexamethasone include perianal pruritus and elevated blood glucose, which can persist for up to 24 hours22 and more pronounced in patients with higher body mass index and higher baseline HBA1c.23 A single pre- or intraoperative antiemetic dose of dexamethasone has not been shown to increase
PHARMACOLOGY FACTS
517
the risk of infection or delay postoperative wound healing.22 Transdermal scopolamine is a M1 receptor antagonist (anticholinergic agent) that effectively reduces PONV when the patch is applied either the day/ evening before surgery or on the day of surgery.24 The patch should not be used in children and should be used with caution in elderly patients or patients with impaired liver or kidney function. In these patients, the dose delivered by the patch is more likely to produce excessive central nervous system effects such as confusion, ataxia, disorientation, restlessness, sedation, and, possibly, acute toxic psychosis. Common adverse effects of transdermal scopolamine include visual disturbances and dry mouth.24 Promethazine is a H1 and M1 receptor antagonist generally reserved for treatment of PONV. For patients who received ondansetron prophylaxis, promethazine 6.25 mg is significantly more effective than ondansetron for treating PONV. Increasing the dose of promethazine does not improve efficacy.25 Adverse effects of promethazine include drowsiness, dry mouth, blurred vision, confusion, and urinary retention. Unintentional intraarterial administration or extravasation of promethazine can cause severe tissue injury. The preferred route of administration is deep IM. If IV administration is used, promethazine should
be diluted (maximum concentration: 25 mg/mL) and administered slowly (maximum rate: 25 mg/ min) through a properly functioning IV.26 Aprepitant is an oral NK-1 receptor antagonist with a long (40 hours) half-life. Aprepitant has been shown to have comparable antiemetic efficacy to ondansetron,27,28 with a more pronounced effect on vomiting than nausea.28 Because clinical experience with aprepitant is limited, its role in routine prophylaxis is not clear.7 Adverse effects of aprepitant include headache, fatigue, weakness, and constipation.
Conclusion There are many stimuli that contribute to PONV and PDNV. Stimulation of one or more of the ‘‘emetogenic receptors’’ (5-HT3, H1, M1, D2, NK1 receptors) can activate the vomiting center. Prophylactic administration of two or more antiemetics that work by a different mode of action (eg, block different emetogenic receptors) is recommended for patients at moderate-to-high risk for PONV. If PONV occurs within 6 hours postoperatively, treatment with an antiemetic that works by a different mode of action is more effective than a repeat dose of the prophylactic antiemetic. If PONV occurs more than 6 hours postoperatively, the emetic episode may be treated with one of the antiemetics administered for prophylaxis.
References 1. Gan TJ. Management of Postoperative Nausea and Vomiting. The ASA Refresher Courses in Anesthesiology CME Program, Chapter 6, Volume 37. The American Society of Anesthesiologists, Inc: 2009; 69-80. 2009;. Available at: www.asa-refresher.com. Accessed September 3, 2014. 2. Horn CC, Wallisch WJ, Homanics GE, Williams JP. Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting. Eur J Pharmacol. 2014;722:55-66. 3. Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol. 2014;722:67-78. 4. McQuaid KR. Drugs used in the treatment of gastrointestinal disease. In: Katzung BG, Masters SB, Trevor PJ, eds. Basic & Clinical Pharmacology, Chapter 62, 12th ed. The McGrawHill Companies Inc; 2012. 5. Apfel CC, L€a€ar€a E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: Conclusions from cross-validations between two centers. Anesthesiology. 1999;91:693-700. 6. Apfel CC, Philip BK, Cakmakkays OS, et al. Who is at risk for postdischarge nausea and vomiting after ambulatory surgery? Anesthesiology. 2012;117:475-486.
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