|Year : 2020 | Volume
| Issue : 1 | Page : 21-24
Metoclopramide-Induced Extrapyramidal Side Effects are Augmented by Domperidone
Ahmad A Almeman
Pharmacology Department, College of Medicine, Qassim University, Al-Qassim, Kingdom of Saudi Arabia
|Date of Submission||21-Sep-2019|
|Date of Decision||23-Oct-2019|
|Date of Acceptance||02-Dec-2019|
|Date of Web Publication||25-Feb-2020|
PhD Ahmad A Almeman
Pharmacology Department, College of Medicine, Qassim University, Al-Qassim
Kingdom of Saudi Arabia
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Metoclopramide is perhaps one of the most common causes of drug-induced movement disorders. It is indicated in several conditions such as nausea, vomiting, diabetic gastroparesis, small bowel intubation, and gastroesophageal reflux. We report a case of a 15-month-old Saudi boy who was first treated for sudden and persistent nausea and vomiting, accompanied by high-grade fever 39.9°C. The physician started treating him with domperidone (Motilium 1 mg/mL oral suspension) 0.25 mg/kg immediate (stat) dose and, hence, he received a total stat dose of 2.5 mg. He was also prescribed paracetamol suppositories for fever at a dose of 15 mg/kg. Later on, another pediatrician decided to administer a stat dose of metoclopramide at approximately 6 p.m. and he received only a single dose of 1 mg metoclopramide I.V. (Primperan), which stopped the nausea and vomiting instantly. The baby was brought back to the same government hospital at 12 a.m., presenting typical extrapyramidal symptoms (EPS). He was treated successfully with only diazepam.
Keywords: Augmentation, domperidone, dystonic reaction, extrapyramidal side effects, metoclopramide
|How to cite this article:|
Almeman AA. Metoclopramide-Induced Extrapyramidal Side Effects are Augmented by Domperidone. Int J Nutr Pharmacol Neurol Dis 2020;10:21-4
|How to cite this URL:|
Almeman AA. Metoclopramide-Induced Extrapyramidal Side Effects are Augmented by Domperidone. Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2021 Feb 27];10:21-4. Available from: https://www.ijnpnd.com/text.asp?2020/10/1/21/279179
| Introduction|| |
Both metoclopramide and domperidone are commonly used antiemetic medications for chemotherapy-induced nausea and vomiting and post-operative nausea. Domperidone is a peripherally acting selective dopamine receptor (D2) antagonist at usual doses whereas metoclopramide is a centrally and peripherally acting dopamine receptor (D2) antagonist. At high doses, it further works as 5-HT3 antagonist. They are indicated in other conditions such as diabetic gastroparesis, small bowel intubation, and gastroesophageal reflux. Most of their pediatric indications are off-label because of increased risk of extrapyramidal symptoms and other side effects., Metoclopramide and domperidone have been reported to cause several severe adverse drug reactions such as extrapyramidal side effects (EPS), tardive dyskinesia, dystonia, and other spasmodic contractions.,,,,,,,,, This case report aims to describe the augmentation effects of metoclopramide by domperidone. This case report was approved from the Ethical Committee of Qassim, Ministry of Health, Saudi Arabia.
| Case history|| |
Herein, we report a case of a 15-month-old Saudi boy who was first treated by a physician from a primary health care center for sudden and persistent nausea and vomiting, accompanied by high-grade fever 39.9°C. The baby had no history of GERD, nor history of prolonged use of any antiemetics. The baby was delivered by caesarian section, at 37 weeks, with a birth weight of approximately 3.2 kg. His weight at the time of this study was approximately 12 kg. He had a positive history of respiratory distress and severe viral infection, which necessitated mechanical ventilation when he was 3 months old. He didn’t show any developmental changes or delays on his growth. His mother reported that he is frequently having seasonal viral infection during winter. The baby and his family have no history of any movement disorders.
The physician started treating him with domperidone (Motilium 1 mg/mL oral suspension) 0.25 mg/kg immediate (stat) dose and, hence, he received a total stat dose of 2.5 mg.
His mother was instructed to repeat the treatment if the boy vomited within 1 h. He was also prescribed paracetamol suppositories for fever at a dose of 15 mg/kg. The first dose of domperidone was administered at approximately 8 a.m. with paracetamol. The fever subsided shortly, but he vomited several times following domperidone administration. Thus, his mother administered two more doses until 12 p.m. without any improvement, as he vomited within minutes. His mother estimated that he vomited 30–45 min after he received the dose. His mother decided to take him to a general government hospital where he was admitted to the observation room.
Several laboratory tests were performed, such as complete blood count (CBC) and general electrolyte determination, including Na, K, and Ca. All his laboratory tests were normal, except for the hemoglobin level, which was 10.9. Thus, the physician started him on omeprazole 1 mg/kg intravenous (IV) stat dose in addition to normal saline (250 mL). Paracetamol was also used to control his fever as needed. Within 3 h in the observation room, the baby persistently vomited several times and the physician did not administer any additional antiemetic agents.
Thus, his mother decided to take him to a pediatrician at another private clinic. The pediatrician decided to administer a stat dose of metoclopramide at approximately 6 p.m. and he only received 1 mg metoclopramide I.V. (Primperan), which stopped the nausea and vomiting instantly. The baby was brought back to the same government hospital at 12 a.m., presenting typical EPS. On examination, he exhibited akathisia, neck dystonia, oculogyric crisis (continuous upward deviation), torticollis, and sialorrhea. The baby had not started walking and, thus, it was difficult to assess his gait. There were no developmental delays on the child and he had no family history of growth delays. However, he could not sit still. There was also an abnormal, but not very significant, lip movement. He was alert and totally oriented at the time of presentation. His blood pressure was 130/85 mmHg, temperature was 36.9°C, and oxygen saturation was 98% (determined using pulse oximetry). The respiratory rate was about 40/min. He didn’t show any signs of respiratory distress.
A nasogastric tube was inserted with 98% oxygen to avoid any potential breathing difficulties and administered 2 mg I.V. diazepam. All the symptoms disappeared within 10 min following diazepam administration. He was admitted for further follow up, and placed on a nothing by mouth protocol (N.P.O.). He started crying at 3 a.m. with normal body movements. He continued sleeping on and off until he was fully awake at approximately 7 a.m. with normal body movements. All the I.V. lines were removed, and he was discharged normally after a supervised full breast-feeding.
A consent form was obtained from the patient’s guardian, which contains all the related data and his permission for publication. The patient was provided assurance regarding anonymity and privacy. The consent was signed by the researcher, patient, and a witness.
| Discussion|| |
Metoclopramide is perhaps one of the most common causes of drug-induced movement disorders. Metoclopramide blocks dopamine D2 receptors and at high doses may antagonize 5-hydroxy tryptamines (5-HT) peripherally. Its half-life (t½) is approximately 5–6 h in adults and 4 h in children. The mechanism of metoclopramide-induced EPS is most likely through blockade of the central dopaminergic receptors involved in motor functions. Other possibilities include genetic predisposition, dopaminergic hypersensitivity, and over activation of the cholinergic system., Most neurological signs and symptoms appear at high doses such as 10 mg daily in adults, especially if prescribed for a long duration.
Although EPS may occur at any age with any dose, several risk factors have been reported including those in pediatric, geriatric, young female, patients with diabetes, cytochrome P450 2D6 (CYP2D6) polymorphism, high I.V. doses, and patients with neurological comorbidities., EPS is likely to occur within 24–48 h after initiation and subside within 24 h following metoclopramide discontinuation. Domperidone blocks dopamine D2 and D3 receptors, which potentiates the effects of metoclopramide. Although EPS is rarely associated with domperidone, especially in adults, as it does not cross the blood–brain barrier. In pediatric patients the blood–brain barrier is not fully formed and, therefore, the risk of EPS might be higher especially with high frequent doses.
The management of chronic use differs from that of acute use. The presentation of chronic use may be delayed for several weeks, and a mere discontinuation may not resolve the symptoms instantly. Conversely, the presentation of involuntary reactions may start typically within a few hours of starting the therapy in acute doses and the symptoms resolve following cessation or administration of stat doses of anticholinergic or diazepam. Our patient had only a single risk factor of being a pediatric.
The patient presented in this case was a 15-month-old boy who received only 1 mg metoclopramide in addition to several doses of domperidone. Although the t½ of metoclopramide is 4 h in pediatric patients, his symptoms started after 6 h, indicating that the t½ may be subject to prolongation under certain conditions. As he received three doses of domperidone and vomited 30–45 min after each dose, the total accumulative concentration in the plasma was not known. It was difficult to estimate the total ingested volume of metoclopramide. However, with the presented EPS and considering that he received only 1 mg metoclopramide, the plasma domperidone concentration should have been at least clinically significant or adequate to synergize metoclopramide.
Although tardive dyskinesia is rarely reversible, most of the neurological symptoms of EPS are reversible following metoclopramide cessation. One of the explanations is overactive transmission of the cholinergic system, which explains why most related research studies have suggested the benefits of anticholinergic medications. The first treatment strategy is to stop metoclopramide immediately or gradually based on the severity of the symptoms. Following continuous use, the symptoms may last for up to 2–3 months and resolve with time. Thus, anticholinergics such as diphenhydramine may be prescribed for a few days to better control the symptoms and prevent a relapse. Benztropine or biperiden may also be used as an alternative anticholinergic., As for dystonic reactions, diphenhydramine is the preferred drug to alleviate dystonic reactions. In our case, I.V. diphenhydramine was not available in the hospital, and the medical team decided to provide diazepam for quick control. Diazepam is indicated when repeated diphenhydramine doses fail to control the symptoms within 30 min.
The patient did not require any further medication when he woke up because the symptoms were fully controlled by the stat dose. Fortunately, this patient did not present with tardive dyskinesia or any life-threatening symptoms such as respiratory distress, and he responded well to the treatment. Several studies and reports have shown that patients who presented with tardive dyskinesia do not respond to the treatment and may experience a degree of incapacitation.,,,,,,To assess the probability of this reaction, the Naranjo algorithm was used. As the drug was not re-administered, no placebo was administered and no plasma concentration was available for this case. Thus, the Naranjo algorithm showed that the drug reaction was probable (score = 8).
This case report is an essential reminder to avoid all potential drug-drug interactions with metoclopramide, which would increase the risk of EPS and its intensity. Moreover, these findings will help simplify the treatment strategy by using only diazepam, especially if diphenhydramine is not available.
The following are the limitations of this case report: (1) it is not possible to generalize the response to both drugs as genetic polymorphism may play a significant role; (2) dose-age response is another essential factor of concern. Depending on the age of the patient, the degree of interaction may differ significantly.
We acknowledge King Saudi Hospital for helping us to collect the data.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Alison B. Martindale: The complete drug reference. Royal Pharmaceutical Society: London 2017, 1747-8
Elek M, Kosa PB, Tamara I, Natasa G, Dragan D. Extrapyramidal side effects of metoclopramide in a child-A case report. Acad J Ped Neonatol 2016;1:555-68.
Campbel D. The management of acute dystonic reactions. Aust Prescr 2001;24:19-20.
Chen JJ. Drug-induced movement disorders. Ment Health Clin 2012;1:167-73.
Kulkarni SK, Naidu PS. Pathophysiology and drug therapy of tardive dyskinesia: current concepts and future perspectives. Drugs Today (Barc) 2003;39:19-49.
Liou YJ, Wang YC, Chen JY et al.
Association analysis of polymorphisms in the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GRIN2B) gene and tardive dyskinesia in schizophrenia. Psychiatry Res 2007;153:271-5.
Pereira SR, Albert M. Anticholinergic discontinuation for antipsychotic-induced extrapyramidal symptoms (Protocol). Cochrane Database of Systematic Reviews 2017 CD012525.
Thomson Reuters Micromedex. Available from: URL: www.micromedex.com
(accessed 3 October 2011).
Pringsheim T, Doja A, Belanger S, Patten S, Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) guideline group. Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth. Paediatr Child Health 2011;16:590-8.
Anderson EP, Freeman EB. Recognition of movement disorders: extrapyramidal side effects and tardive dyskinesia. Would you recognize them if you see them? Pract Gastroenterol 2004;28:14-26.
Rao AS, Camilleri M. Review article: metoclopramide and tardive dyskinesia. Ailment Pharmacol Ther 2010;31:11-9.
American Society of Health System Pharmacists. AHFS Drug Information 2010. Bethesda, MD; 2010.
Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug insight: from disturbed motility to disordered movement–A review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol Hepatol 2006;3:138-48.
Karagoz G, Kadanali A, Dede B, Anadol U, Yucel M, Bektasoglu MF. Metoclopramide-induced acute dystonic reaction: a case report. Eurasian J Med 2013;45:58-9.
Oyewole A, Adelufosi A, Abayomi O. Acute dystonic reaction as medical emergency: a report of two cases. Ann Med Health Sci Res 2013;3:453-55.
] [Full text]
Ganzini L, Casey DE, Hoffman WF, McCall AL. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 1993;153:1469-75.
Kaplan S. Metoclopramide: drug use data review (Myzan®
, NDA 21-645). 2005.
Yis U, Ozdemir D, Duman M, Unal N. Metoclopramide induced dystonia in children: two case reports. Eur J Emerg Med 2005;12:117-9.
Low LC, Goel KM. Metoclopramide poisoning in children. Arch Dis Child 1980;55:310-2.
Freudenreich O. Atypical laryngeal dystonia caused by an antiemetic. Am Fam Physician 2004;69:1623.
Comfort S, Dorrell D, Meireis S, Fine J. MOdifiedNARanjo Causality Scale for ICSRs (MONARCSi): A decision support tool for safety scientists. Drug Saf 2018;41:1073-85.