METOCLOPRAMIDE AND RELATED AGENTS
- USES: Metoclopramide is an antiemetic and a prokinetic gastrointestinal agent. It is used in the treatment of diabetic gastroparesis, prevention of postoperative or chemotherapy-induced nausea and vomiting, gastroesophageal reflux, small bowl intubation, and radiological examination of the gastrointestinal tract. PHARMACOLOGY: Metoclopramide blocks dopamine receptors, and in higher doses also blocks serotonin receptors in the chemoreceptor trigger zone of the central nervous system. It enhances the response to acetylcholine of tissue in the upper gastrointestinal tract, causing enhanced motility and accelerated gastric emptying, and increases lower esophageal sphincter tone. It does not increase stimulation of gastric, biliary, or pancreatic secretions. TOXICOLOGY: Its mechanism of toxicity is likely secondary to its mechanism of action, especially its dopamine antagonism. EPIDEMIOLOGY: There are adverse reactions/unintentional exposures reported every year. Intentional overdose does occur, but is relatively rare, and toxicity is generally mild. TOXICITY: Inadvertent overdose in newborns and infants has resulted in severe methemoglobinemia and opisthotonic posturing. Common toxic effects include restlessness, drowsiness, insomnia, headache, confusion, dizziness and acute dystonic reactions. Acute dystonic reactions are more common in children and young adults, whereas prolonged reactions are more common in elderly patients. Most dystonic reactions resolve within 12 to 48 hours but may last for months but may last for months after discontinuation of chronic therapy. Neuroleptic malignant syndrome is an idiosyncratic reaction that may develop after a single dose of medication but also can occur after overdose or prolonged therapy. ADVERSE EFFECTS: There are many different adverse reactions that can occur with therapeutic dosing of metoclopramide. CARDIOVASCULAR: AV block, bradycardia, edema, flushing (especially after high IV dosing), hypertension, hypotension, and supraventricular tachycardia may occur. Angioneurotic edema is rare. CENTRAL NERVOUS SYSTEM: The most commonly observed (in up to 70% of patients) adverse effects. These effects are dose and age-related. They include acute dystonic reactions (in up to 25% of patients) and about 10% of patients exhibit fatigue, lassitude, or restlessness. Patients also exhibit akathisia, confusion, depression, dizziness, headache, insomnia, Parkinsonian-like symptoms, suicidal ideation, seizure, and tardive dyskinesia. Rarely, they exhibit hallucinations and neuroleptic malignant syndrome. DERMATOLOGIC: Rash and urticaria may occur. ENDOCRINE AND METABOLIC: Amenorrhea, galactorrhea, gynecomastia, and hyperprolactinemia may occur with chronic therapy. GASTROINTESTINAL: Diarrhea and nausea may occur. GENITOURINARY: Incontinence and urinary frequency may occur. Impotence may occur with chronic therapy. HEMATOLOGIC: Agranulocytosis, leukopenia, neutropenia, porphyria, methemoglobinemia, and sulfhemoglobinemia have occurred. IMMUNOLOGIC: Allergic reactions may occur. EYES: Visual disturbances have also been reported. RESPIRATORY: The most common respiratory adverse reaction is bronchospasm, however, laryngeal edema and laryngospasm have rarely occurred. Parenteral formulations that contain sulfite preservatives may precipitate bronchospasm in susceptible individuals.
Range of Toxicity:
METOCLOPRAMIDE AND RELATED AGENTS
- TOXICITY: Mild toxicity has occurred even at therapeutic doses. Compared to other antiemetics, it has a relatively low therapeutic index. Inadvertent ingestions of 3 mg/kg in children have caused extrapyramidal symptoms, and ingestions of 4.6 to 6.6 mg/kg in adults have resulted in neurologic symptoms with recovery. An adult who ingested 36 tablets of metoclopramide developed symptoms of drowsiness, confusion, and traces of albumin in the urine. DOMPERIDONE: A 3-month-old infant developed intense irritability, excessive crying, a classic oculogyric crises, and dystonic cycling movements, supraventricular tachycardia, and elevated serum prolactin several hours after receiving a large dose of domperidone (25 mg 2 times in 4 hours; total dose: 50 mg or more than 10 mg/kg in 4 hours instead of the prescribed 0.5 mg/kg/dose; a dose of 2.5 mL equals to 2.5 mg of domperidone). She recovered following supportive care. THERAPEUTIC DOSE: ADULTS: ORAL: 10 to 15 mg up to 4 times daily. IV or IM: Varies by indication: 10 to 20 mg as a single dose or slowly over 1 to 2 minutes OR for chemotherapy-induced nausea and vomiting: 1 to 2 mg/kg/dose IV over 15 min administered 30 min prior to chemotherapy and then every 2 hours for 2 doses, then every 3 hours for 3 doses. CHILDREN: ORAL: GASTROESOPHAGEAL REFLUX: The safety and efficacy of oral metoclopramide in pediatric patients have not been established by the manufacturer. However, the following doses have been used: Infants and children: 0.1 mg/kg/dose orally 3 to 4 times a day. Doses up to 0.3 mg/kg/dose 4 times a day are more effective, but are associated with a much higher incidence of side effects. IV: PREVENTION OF CHEMOTHERAPY-INDUCED EMESIS: 2.5 mg/kg/dose IV for one to two doses 30 minutes before chemotherapy and two hours later; then 0.4 mg/kg/hour IV by continuous infusion or 1 mg/kg/dose. INTESTINAL INTUBATION: (14 years and older) a single 10 mg IV dose over 1 to 2 minutes; (6 to 14 years of age) a single 2.5 mg to 5 mg IV dose over 1 to 2 minutes; (under 6 years of age) a single 0.1 mg/kg IV dose over 1 to 2 minutes.
METOCLOPRAMIDE AND RELATED AGENTS
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Routine decontamination is not recommended as most toxicity is mild. Dystonic reactions in adults can be treated with benztropine 1 to 4 mg IV (max 6 mg/day) and/or diphenhydramine 25 to 50 mg/dose IV over 2 minutes (maximum 100 mg/dose, 400 mg/day) in adults. Dosing of diphenhydramine in children is 1.25 mg/kg/dose IV over 2 minutes with a maximum daily dosing of 300 mg/day. Patients may require treatment for several days to avoid recurrence of dystonic reactions. MANAGEMENT OF SEVERE TOXICITY: Severe toxicity, though rare, includes cardiovascular and CNS effects such as bradycardia, hypotension, hypertension, seizures, and cardiac arrest. Standard treatment is indicated such as atropine for bradycardia and fluids and pressors for hypotension. Seizures should be managed with benzodiazepines (eg, diazepam 5 to 10 mg or lorazepam 2 to 4 mg every 10 to 15 minutes for adults as needed; for children, 0.2 to 0.5 mg/kg diazepam or lorazepam 0.05 to 0.1 mg/kg every 5 minutes as needed). Consider giving phenobarbital or propofol if seizures continue to occur despite benzodiazepine therapy. Neuroleptic malignant syndrome can be treated with good supportive care and intravenous benzodiazepines; consider bromocriptine, amantadine or dantrolene if not responding to benzodiazepines. Methemoglobinemia can be treated with 1 to 2 mg/kg of 1% methylene blue IV in symptomatic patients.
- Decontamination: PREHOSPITAL: Decontamination is generally not indicated as toxicity is usually not severe. HOSPITAL: In general, decontamination is not indicated for this overdose, but may be considered for massive overdoses that present early. Activated charcoal should be considered if the patient is awake and cooperative and if the ingestion was relatively recent. Gastric lavage, whole bowel irrigation, or multiple doses of charcoal are not indicated.
- Airway management: Endotracheal intubation and mechanical ventilation may be necessary if the patient develops respiratory distress or fails to protect his or her airway secondary to altered mental status.
- Antidote: None.
- Monitoring of patient: No specific laboratory studies are needed in most patients. Metoclopramide levels are not readily available and not useful in managing toxicity. Monitor vital signs, mental status, and for the development of dystonic reactions. Monitor CBC with differential, CPK, and liver enzymes in symptomatic patients. Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.
- Enhanced elimination procedure: There is no role for dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal.
- Patient disposition: HOME CRITERIA: Asymptomatic patients with inadvertent exposures may be monitored at home. All other patients may require observation. OBSERVATION CRITERIA: Intentional overdoses or patients with symptoms should be observed for 4 to 6 hours, and may be discharged if only mild symptoms persist. ADMISSION CRITERIA: Patients with continued/worsening symptoms after observation for several hours should be admitted for further monitoring, and depending on the severity of their symptoms, may merit an ICU bed. Criteria for discharge should be resolution of symptoms. CONSULT CRITERIA: Contact your local poison center or toxicologist for any concerns. The mainstay of treatment is good symptomatic and supportive care.