Pharma cology Matters
DOPAMINE ANTAGONISTS FOR NAUSEA AND VOMITING: SPECIAL CONSIDERATIONS
Mark Welliver, DNP, CRNA, ARNP
Column Editor
D
opamine is a neurotransmitter responsible for many functions throughout the human body. In the brain, dopamine plays several crucial roles in motor control, cognitive function, pleasure/ reward system, hormonal control, and nausea and vomiting (N&V). Five different subtypes of dopamine receptors are known (D1–D5). There are subtle differences among these subtypes of receptors. The two most prevalent dopamine receptors in the brain are D1 and D2. Specific dopamine D2 subtype receptors are located in the chemoreceptor trigger zone (CTZ) and respond to dopamine released from nerve endings. Often the origin of CTZ stimulation is from the gastrointestinal (GI) tract. Dopamine and serotonin are two neurotransmitters released by GI irritation. Although serotonin antagonists (5HT3 blockers) have become the first-line drug choice to treat N&V, dopamine antagonists, specifically D2 antagonists, remain effective drug choices, especially if serotonin antagonists fail. Administration of a D2 antagonist is highly effective for treating N&V, but because of dopamine’s close relationship with so many other brain functions, disruption can be expected. Specifically, extrapyramidal reactions (abnormal motor function) and confusion may occur. There are three main molecular drug structures that exert D2 antagonism, phenothiazines, substituted benzamides, and butyrophenones. The following are some of the most commonly considered D2 antagonist drugs used for treating N&V. Each has its own unique benefits as well as side effects to consider. Phenothiazines: promethazine (Phenergan), prochlorperazine (Compazine), Substituted benzamide: metoclopramide (Reglan), Butyrophenone: droperidol (Inapsine).
Phenothiazines THE OFFICIAL JOURNAL OF THE SOCIETY OF GASTROENTEROLOGY NURSES AND ASSOCIATES, INC., AND THE CANADIAN SOCIETY OF GASTROENTEROLOGY NURSES AND ASSOCIATES
Promethazine (Phenergan) Promethazine is used to treat N&V and motion sickness. Promethazine is also used as a sedative-hypnotic because of its ability to block dopamine receptors (Figure 1). Allergic reactions caused by histamine release may be
DEDICATED TO THE SAFE AND EFFECTIVE PRACTICE OF GASTROENTEROLOGY AND ENDOSCOPY NURSING
VOLUME 37
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NUMBER 5
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The author declares no conflict of interest. DOI: 10.1097/SGA.0000000000000068
SEPTEMBER/OCTOBER 2014
361
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GNJ-D-14-00083.indd 361
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Pharmacology Matters
FIGURE 1. Phenothiazines: Promethazine (Phenergan) and prochlorperazine (Compazine).
treated by promethazine through blocade of histamine receptors (H1 subtype). It may be administered orally, rectally, intramuscularly, or intravenously. As with most drugs that contain a phenol group, promethazine is irritating to blood vessels and has caused serious extravasation injuries, some requiring amputation (Grissinger, 2009) Because of this risk, the following strategies have been recommended when administering this drug: Consider nonintravenous route, use intramuscular injection into a large muscle, administer intravenously into a large vessel with verified patent catheter and flowing intravenous fluid, limit dose to 25 mg or less, dilute dose, inject slowly, consider other drug therapies (Grissinger, 2009). Additional considerations with promethazine include risk of respiratory suppression (avoid use in children) and cholestatic jaundice (Phenergan, 2014). Promethazine antiemetic effects and sedative effects last 4–6 hours. It is metabolized by the liver with metabolites excreted by the kidneys (Grissinger, 2009; Phenergan, 2014).
Prochlorperazine (Compazine) Prochlorperazine (Compazine) is classified structurally as a phenothiazine and is used primarily as an antipsychotic. The reason that this drug has two distinct treatment applications is related to the significant roles the neurotransmitter dopamine plays in brain functioning.
Substituted Benzamide Metoclopramide (Reglan) Metoclopramide works both centrally in the brain and peripherally in the GI system (Figure 2). Centrally, metoclopramide blocks D2 receptors and weakly blocks 5HT3 receptors (Albibi & McCallum, 1983). Peripherally, metoclopramide inhibits D2 receptors. This 5HT3 blockade causes increased lower esopha-
FIGURE 2. Substituted benzamide: Metoclopramide (Reglan).
geal tone, gastric motility, and emptying (Albibi & McCallum, 1983; Fernandez & Massingham, 1985; Lee & Kuo, 2010; Tonini et al., 2004). It is likely that the neurotransmitter acetylcholine (ACh) is enhanced by D2 blockade in the GI tract. Therefore, ACh is able to stimulate receptors to also improve gastric motility. Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system, which is responsible for gastric motility and digestion. Increased or enhanced function of ACh would be expected to stimulate GI function. The improved gastric motility likely has an antiemetic effect by attenuating neuronal stimulation to the CTZ. Metoclopramide may be administered orally or intravenously. After oral ingestion, about 80% of the drug is available compared with an equal dose administered intravenously. It is well distributed throughout the body. About 30% of the drug is protein bound and 80% is excreted via the kidneys (Reglan, 2014). Metoclopramide may be used to improve gastric motility in diabetic gastroparesis or to assist passing small bowel tubes, to improve spread of radiopaque substances such as barium, and prophylaxis or treatment for postoperative or chemotherapy-induced N&V (Lee & Kuo, 2010). Ten to 20 mg are the usual dose of metoclopramide. Higher doses may be used but increase the risk of side effects. Serious adverse effects include extrapyramidal reactions (muscular restlessness, Parkinson’s-like motions, and tardive dyskinesia). Muscular restlessness,
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Pharmacology Matters like uncontrollable leg shaking, may be treated with diphenhydramine (Benadryl) 50 mg intramuscular or intravenous (IV) (Reglan, 2014). Muscular restlessness may be seen after only one dose. Parkinson’s-like syndrome (slower uncoordinated movements or rigidity) may manifest within the first 6 months of continual use. These symptoms will reside within months of discontinuing the drug. A more serious and possibly permanent adverse effect is tardive dyskinesia, which also may occur with long-term use. Tardive dyskinesia manifests mostly as involuntary movement of facial muscles and tongue, although the extremities may also be affected. A possible underlying difference between Parkinson’s-like side effects and tardive dyskinesia is the drug’s effect on dopamine receptors and dopamine pathways in the brain. Metoclopramide, as a dopamine antagonist, blocks dopamine receptors from being stimulated. Dopamine in the basal ganglia of the brain is responsible for suppressing any extraneous or discordant impulses to our muscles. The effect is smooth cerebral-motor (brain-muscle) communication and movement. Metoclopramide, by blocking dopamine’s suppressive effect, may allow excessive impulse outflow causing “extra” movements and thus Parkinson’s-like symptoms. Metoclopramide’s blocking of dopamine may also cause heightened sensitivity of dopamine receptors within the brain or promote genetic polymorphism of subsequent receptor production. The exact cause remains unknown and treatment primarily consists of discontinuing the drug to allow symptoms to decrease.
Butyrophenones Droperidol (Inapsine) Butyrophenones have a significant incidence of disorientation, confusion, and delirium associated with their use in addition to antiemetic properties (Figure 3). The two most common drugs in this class are droperidol and Haloperidol. Haloperidol is most useful as an antipsychotic. Droperidol has more effective antiemetic effect especially at low doses. Intravenous doses used to treat N&V are low (0.625 mg) compared with doses that result in disorientation effects (>1.0 mg). Droperidol is administered intravenously or intramuscularly; the intravenous route is effective for treatment of N&V within minutes. Droperidol is administered intravenously as both prophylaxis and treatment of N&V. The usual dose for N&V is 0.625 mg IV. The initial dose is repeatable to a maximum dose of 2.5 mg, but increased doses increase the risk of adverse effects, including delirium, confusion, and agitation. Droperidol is metabolized by the liver. Meta-analyses have confirmed this antiemetic effectiveness of droperidol (Domino, Anderson, Polissar, & Posner, 1999; Ebhart, VOLUME 37
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FIGURE 3. Butyrophenones: Droperidol (Inapsine) and Haloperidol (Haldol).
Morin, Seeling, Bothner, & Georgieff, 1999; Droperidol, 2014). Despite this, clinicians are often hesitant to use droperidol as a first-line medication treatment for emesis. In addition, the Food and Drug Administration (FDA) has issued a “black box” warning for droperidol because of the potential for QT prolongation on electrocardiogram. Although doses greater than 0.1 mg/kg (8–10+ mg total), which far exceeds antiemetic doses, produced QT prolongation in patients, no dysrhythmias were discovered in noncardiac or nonconduction defect patients (Lischke, 1994). These same authors concluded that avoidance of droperidol should not be solely because of QT prolongation. “It seems that QTc [QT-calculated] interval prolongation after IV [intravenous] DRO [peridol] is no reason to avoid the use of this drug. This assumption is supported by the observation that multiple anesthetics may cause equivalent or concomitant alterations of the QTc interval without having been linked to an increased perioperative morbidity in otherwise healthy patients” (Lischke et al., 1994, p. 986). It is interesting to note here, along with droperidol, that that the FDA has recently expressed concern with the 5HT3 blocker ondansetron (Zofran) because of known QTc prolongation (FDA, 2011). Same pharmacologic class drugs dolasetron (Anzemet) and granisetron (Kytril) should raise similar concern. Appropriate awareness and consideration of these concerns are warranted before administering either of these antiemetic classes (dopamine and serotonin blockers). The long history of each of these drugs’ successful use and low incidence of dysrhythmias in patients without underlying conduction disturbances, particularly QT abnormalities, should also be considered. The known incidence of QT prolongation, however small, was reviewed in initial clinical trials of the 5HT3 blockers but not with original droperidol study warranting the more recent notifications to healthcare providers 363
Copyright © 2014 Society of Gastroenterology Nurses and Associates. Unauthorized reproduction of this article is prohibited.
GNJ-D-14-00083.indd 363
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Pharmacology Matters (McCarthy et al., 2014). Possibly, had more formal studies of the QT prolongation concerns been addressed prior to FDA drug approval, the current warning could not have been necessary. Nonetheless, the significant risks posed by QT prolongation necessitate an understanding of this side effect and its clinical impact.
Summary The dopamine antagonists, particularly droperidol, are effective at treating N&V. Because dopamine plays many roles in the body, especially in the brain, a degree of alteration in mental status should be expected, especially with higher doses. Other less frequent side effects include QT prolongation. When given for non– chemotherapy-induced N&V treatment QT prolongation is rare. Higher doses warrant clinical awareness and ability to identify and treat prolonged QT and its sequelae. Invited authors for a following column will discuss QT prolongation and implications.
REFERENCES Albibi, R., & McCallum, R. W. (1983). Metoclopramide: Pharmacology and clinical application. Annals of Internal Medicine, 98(1), 86–95. Domino, K. B., Anderson, E. A., Polissar, N. L., & Posner, K. L. (1999). Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: A meta-analysis. Anesthesia and Analgesia, 88(6), 1370–1379. Droperidol (Inapsine injection). (2001). Taylor pharmaceuticals. Retrieved June 16, 2014, from http://www.fda.gov/ohrms/ dockets/ac/03/briefing/4000B1_08_Droperidol%20Insert%20 After%2012-01.pdf
Ebhart, L. H., Morin, A. M., Seeling, W., Bothner, U., & Georgieff, M. (1999). Meta-analysis of controlled randomized studies on droperidol for prevention of postoperative phase vomiting and nausea. Änasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 34(9), 528–536. Fernandez, A. G., & Massingham, R. (1985). Peripheral receptor populations involved in the regulation of gastrointestinal motility and the pharmacological actions of metoclopramide-like drugs. Life Sciences, 36(1), 1–14. Food and Drug Administration. (2011). Drugs safety announcement. Retrieved April 2, 2014, from http://www.fda.gov/drugs/ drugsafety/ucm271913.htm Grissinger, M. (2009). Preventing serious tissue injury with promethazine (Phenergan). Pharmacy and Therapeutics, 34(4), 175–176. Lee, A., & Kuo, B. (2010). Metoclopramide in the treatment of diabetic gastroparesis. Expert Review of Endocrinology & Metabolism, 5(5), 653–662. Lischke, V., Behne, M., Doelken, P., Schledt, U., Probst, S., & Vettermann, J. (1994). Droperidol causes a dose dependent prolongation of the QT interval. Anesthesia and Analgesia, 79(5), 983–986. McCarthy, J., et al. (2014, April). Expert panel at University of North Florida Patient Safety Conference proceedings. Amelia Island, FL. Phenergan (promethazine HCl). (2014). [Drug information]. Philadelphia, PA: Wyeth. Retrieved May 13, 2014, from http://www .accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf Reglan (metoclopramide). (2014). Baxter Healthcare Corporation. Deerfield, IL: Reglan. Retrieved from http://www.accessdata .fda.gov/drugsatfda_docs/label/2010/017862s063lbl.pdf Tonini, M., Cipollina, L., Poluzzi, E., Crema, F., Corazza, G. R., & De Ponti, F. (2004). Review article: Clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Alimentary Pharmacology and Therapeutics, 19(4), 379–390.
364 Copyright © 2014 Society of Gastroenterology Nurses and Associates
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DOPAMINE ANTAGONISTS FOR NAUSEA AND VOMITING: SPECIAL CONSIDERATIONS
Mark Welliver, DNP, CRNA, ARNP
Column Editor
D
opamine is a neurotransmitter responsible for many functions throughout the human body. In the brain, dopamine plays several crucial roles in motor control, cognitive function, pleasure/ reward system, hormonal control, and nausea and vomiting (N&V). Five different subtypes of dopamine receptors are known (D1–D5). There are subtle differences among these subtypes of receptors. The two most prevalent dopamine receptors in the brain are D1 and D2. Specific dopamine D2 subtype receptors are located in the chemoreceptor trigger zone (CTZ) and respond to dopamine released from nerve endings. Often the origin of CTZ stimulation is from the gastrointestinal (GI) tract. Dopamine and serotonin are two neurotransmitters released by GI irritation. Although serotonin antagonists (5HT3 blockers) have become the first-line drug choice to treat N&V, dopamine antagonists, specifically D2 antagonists, remain effective drug choices, especially if serotonin antagonists fail. Administration of a D2 antagonist is highly effective for treating N&V, but because of dopamine’s close relationship with so many other brain functions, disruption can be expected. Specifically, extrapyramidal reactions (abnormal motor function) and confusion may occur. There are three main molecular drug structures that exert D2 antagonism, phenothiazines, substituted benzamides, and butyrophenones. The following are some of the most commonly considered D2 antagonist drugs used for treating N&V. Each has its own unique benefits as well as side effects to consider. Phenothiazines: promethazine (Phenergan), prochlorperazine (Compazine), Substituted benzamide: metoclopramide (Reglan), Butyrophenone: droperidol (Inapsine).
Phenothiazines THE OFFICIAL JOURNAL OF THE SOCIETY OF GASTROENTEROLOGY NURSES AND ASSOCIATES, INC., AND THE CANADIAN SOCIETY OF GASTROENTEROLOGY NURSES AND ASSOCIATES
Promethazine (Phenergan) Promethazine is used to treat N&V and motion sickness. Promethazine is also used as a sedative-hypnotic because of its ability to block dopamine receptors (Figure 1). Allergic reactions caused by histamine release may be
DEDICATED TO THE SAFE AND EFFECTIVE PRACTICE OF GASTROENTEROLOGY AND ENDOSCOPY NURSING
VOLUME 37
|
NUMBER 5
|
The author declares no conflict of interest. DOI: 10.1097/SGA.0000000000000068
SEPTEMBER/OCTOBER 2014
361
Copyright © 2014 Society of Gastroenterology Nurses and Associates. Unauthorized reproduction of this article is prohibited.
GNJ-D-14-00083.indd 361
24/09/14 8:27 PM
Pharmacology Matters
FIGURE 1. Phenothiazines: Promethazine (Phenergan) and prochlorperazine (Compazine).
treated by promethazine through blocade of histamine receptors (H1 subtype). It may be administered orally, rectally, intramuscularly, or intravenously. As with most drugs that contain a phenol group, promethazine is irritating to blood vessels and has caused serious extravasation injuries, some requiring amputation (Grissinger, 2009) Because of this risk, the following strategies have been recommended when administering this drug: Consider nonintravenous route, use intramuscular injection into a large muscle, administer intravenously into a large vessel with verified patent catheter and flowing intravenous fluid, limit dose to 25 mg or less, dilute dose, inject slowly, consider other drug therapies (Grissinger, 2009). Additional considerations with promethazine include risk of respiratory suppression (avoid use in children) and cholestatic jaundice (Phenergan, 2014). Promethazine antiemetic effects and sedative effects last 4–6 hours. It is metabolized by the liver with metabolites excreted by the kidneys (Grissinger, 2009; Phenergan, 2014).
Prochlorperazine (Compazine) Prochlorperazine (Compazine) is classified structurally as a phenothiazine and is used primarily as an antipsychotic. The reason that this drug has two distinct treatment applications is related to the significant roles the neurotransmitter dopamine plays in brain functioning.
Substituted Benzamide Metoclopramide (Reglan) Metoclopramide works both centrally in the brain and peripherally in the GI system (Figure 2). Centrally, metoclopramide blocks D2 receptors and weakly blocks 5HT3 receptors (Albibi & McCallum, 1983). Peripherally, metoclopramide inhibits D2 receptors. This 5HT3 blockade causes increased lower esopha-
FIGURE 2. Substituted benzamide: Metoclopramide (Reglan).
geal tone, gastric motility, and emptying (Albibi & McCallum, 1983; Fernandez & Massingham, 1985; Lee & Kuo, 2010; Tonini et al., 2004). It is likely that the neurotransmitter acetylcholine (ACh) is enhanced by D2 blockade in the GI tract. Therefore, ACh is able to stimulate receptors to also improve gastric motility. Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system, which is responsible for gastric motility and digestion. Increased or enhanced function of ACh would be expected to stimulate GI function. The improved gastric motility likely has an antiemetic effect by attenuating neuronal stimulation to the CTZ. Metoclopramide may be administered orally or intravenously. After oral ingestion, about 80% of the drug is available compared with an equal dose administered intravenously. It is well distributed throughout the body. About 30% of the drug is protein bound and 80% is excreted via the kidneys (Reglan, 2014). Metoclopramide may be used to improve gastric motility in diabetic gastroparesis or to assist passing small bowel tubes, to improve spread of radiopaque substances such as barium, and prophylaxis or treatment for postoperative or chemotherapy-induced N&V (Lee & Kuo, 2010). Ten to 20 mg are the usual dose of metoclopramide. Higher doses may be used but increase the risk of side effects. Serious adverse effects include extrapyramidal reactions (muscular restlessness, Parkinson’s-like motions, and tardive dyskinesia). Muscular restlessness,
362 Copyright © 2014 Society of Gastroenterology Nurses and Associates
Gastroenterology Nursing
Copyright © 2014 Society of Gastroenterology Nurses and Associates. Unauthorized reproduction of this article is prohibited.
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Pharmacology Matters like uncontrollable leg shaking, may be treated with diphenhydramine (Benadryl) 50 mg intramuscular or intravenous (IV) (Reglan, 2014). Muscular restlessness may be seen after only one dose. Parkinson’s-like syndrome (slower uncoordinated movements or rigidity) may manifest within the first 6 months of continual use. These symptoms will reside within months of discontinuing the drug. A more serious and possibly permanent adverse effect is tardive dyskinesia, which also may occur with long-term use. Tardive dyskinesia manifests mostly as involuntary movement of facial muscles and tongue, although the extremities may also be affected. A possible underlying difference between Parkinson’s-like side effects and tardive dyskinesia is the drug’s effect on dopamine receptors and dopamine pathways in the brain. Metoclopramide, as a dopamine antagonist, blocks dopamine receptors from being stimulated. Dopamine in the basal ganglia of the brain is responsible for suppressing any extraneous or discordant impulses to our muscles. The effect is smooth cerebral-motor (brain-muscle) communication and movement. Metoclopramide, by blocking dopamine’s suppressive effect, may allow excessive impulse outflow causing “extra” movements and thus Parkinson’s-like symptoms. Metoclopramide’s blocking of dopamine may also cause heightened sensitivity of dopamine receptors within the brain or promote genetic polymorphism of subsequent receptor production. The exact cause remains unknown and treatment primarily consists of discontinuing the drug to allow symptoms to decrease.
Butyrophenones Droperidol (Inapsine) Butyrophenones have a significant incidence of disorientation, confusion, and delirium associated with their use in addition to antiemetic properties (Figure 3). The two most common drugs in this class are droperidol and Haloperidol. Haloperidol is most useful as an antipsychotic. Droperidol has more effective antiemetic effect especially at low doses. Intravenous doses used to treat N&V are low (0.625 mg) compared with doses that result in disorientation effects (>1.0 mg). Droperidol is administered intravenously or intramuscularly; the intravenous route is effective for treatment of N&V within minutes. Droperidol is administered intravenously as both prophylaxis and treatment of N&V. The usual dose for N&V is 0.625 mg IV. The initial dose is repeatable to a maximum dose of 2.5 mg, but increased doses increase the risk of adverse effects, including delirium, confusion, and agitation. Droperidol is metabolized by the liver. Meta-analyses have confirmed this antiemetic effectiveness of droperidol (Domino, Anderson, Polissar, & Posner, 1999; Ebhart, VOLUME 37
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SEPTEMBER/OCTOBER 2014
FIGURE 3. Butyrophenones: Droperidol (Inapsine) and Haloperidol (Haldol).
Morin, Seeling, Bothner, & Georgieff, 1999; Droperidol, 2014). Despite this, clinicians are often hesitant to use droperidol as a first-line medication treatment for emesis. In addition, the Food and Drug Administration (FDA) has issued a “black box” warning for droperidol because of the potential for QT prolongation on electrocardiogram. Although doses greater than 0.1 mg/kg (8–10+ mg total), which far exceeds antiemetic doses, produced QT prolongation in patients, no dysrhythmias were discovered in noncardiac or nonconduction defect patients (Lischke, 1994). These same authors concluded that avoidance of droperidol should not be solely because of QT prolongation. “It seems that QTc [QT-calculated] interval prolongation after IV [intravenous] DRO [peridol] is no reason to avoid the use of this drug. This assumption is supported by the observation that multiple anesthetics may cause equivalent or concomitant alterations of the QTc interval without having been linked to an increased perioperative morbidity in otherwise healthy patients” (Lischke et al., 1994, p. 986). It is interesting to note here, along with droperidol, that that the FDA has recently expressed concern with the 5HT3 blocker ondansetron (Zofran) because of known QTc prolongation (FDA, 2011). Same pharmacologic class drugs dolasetron (Anzemet) and granisetron (Kytril) should raise similar concern. Appropriate awareness and consideration of these concerns are warranted before administering either of these antiemetic classes (dopamine and serotonin blockers). The long history of each of these drugs’ successful use and low incidence of dysrhythmias in patients without underlying conduction disturbances, particularly QT abnormalities, should also be considered. The known incidence of QT prolongation, however small, was reviewed in initial clinical trials of the 5HT3 blockers but not with original droperidol study warranting the more recent notifications to healthcare providers 363
Copyright © 2014 Society of Gastroenterology Nurses and Associates. Unauthorized reproduction of this article is prohibited.
GNJ-D-14-00083.indd 363
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Pharmacology Matters (McCarthy et al., 2014). Possibly, had more formal studies of the QT prolongation concerns been addressed prior to FDA drug approval, the current warning could not have been necessary. Nonetheless, the significant risks posed by QT prolongation necessitate an understanding of this side effect and its clinical impact.
Summary The dopamine antagonists, particularly droperidol, are effective at treating N&V. Because dopamine plays many roles in the body, especially in the brain, a degree of alteration in mental status should be expected, especially with higher doses. Other less frequent side effects include QT prolongation. When given for non– chemotherapy-induced N&V treatment QT prolongation is rare. Higher doses warrant clinical awareness and ability to identify and treat prolonged QT and its sequelae. Invited authors for a following column will discuss QT prolongation and implications.
REFERENCES Albibi, R., & McCallum, R. W. (1983). Metoclopramide: Pharmacology and clinical application. Annals of Internal Medicine, 98(1), 86–95. Domino, K. B., Anderson, E. A., Polissar, N. L., & Posner, K. L. (1999). Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: A meta-analysis. Anesthesia and Analgesia, 88(6), 1370–1379. Droperidol (Inapsine injection). (2001). Taylor pharmaceuticals. Retrieved June 16, 2014, from http://www.fda.gov/ohrms/ dockets/ac/03/briefing/4000B1_08_Droperidol%20Insert%20 After%2012-01.pdf
Ebhart, L. H., Morin, A. M., Seeling, W., Bothner, U., & Georgieff, M. (1999). Meta-analysis of controlled randomized studies on droperidol for prevention of postoperative phase vomiting and nausea. Änasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 34(9), 528–536. Fernandez, A. G., & Massingham, R. (1985). Peripheral receptor populations involved in the regulation of gastrointestinal motility and the pharmacological actions of metoclopramide-like drugs. Life Sciences, 36(1), 1–14. Food and Drug Administration. (2011). Drugs safety announcement. Retrieved April 2, 2014, from http://www.fda.gov/drugs/ drugsafety/ucm271913.htm Grissinger, M. (2009). Preventing serious tissue injury with promethazine (Phenergan). Pharmacy and Therapeutics, 34(4), 175–176. Lee, A., & Kuo, B. (2010). Metoclopramide in the treatment of diabetic gastroparesis. Expert Review of Endocrinology & Metabolism, 5(5), 653–662. Lischke, V., Behne, M., Doelken, P., Schledt, U., Probst, S., & Vettermann, J. (1994). Droperidol causes a dose dependent prolongation of the QT interval. Anesthesia and Analgesia, 79(5), 983–986. McCarthy, J., et al. (2014, April). Expert panel at University of North Florida Patient Safety Conference proceedings. Amelia Island, FL. Phenergan (promethazine HCl). (2014). [Drug information]. Philadelphia, PA: Wyeth. Retrieved May 13, 2014, from http://www .accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf Reglan (metoclopramide). (2014). Baxter Healthcare Corporation. Deerfield, IL: Reglan. Retrieved from http://www.accessdata .fda.gov/drugsatfda_docs/label/2010/017862s063lbl.pdf Tonini, M., Cipollina, L., Poluzzi, E., Crema, F., Corazza, G. R., & De Ponti, F. (2004). Review article: Clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Alimentary Pharmacology and Therapeutics, 19(4), 379–390.
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