Continuing Education Activity

Metoclopramide is a dopamine receptor antagonist and has been approved by the FDA to treat nausea and vomiting in patients with gastroesophageal reflux disease or diabetic gastroparesis by increasing gastric motility. It is also used to control nausea and vomiting in chemotherapy patients. Additionally, metoclopramide can be administered prophylactically to prevent nausea and vomiting in postoperative patients when nasogastric suction is contraindicated or unavailable and has shown surprising success in treating migraines; however, the FDA has not explicitly approved it for these other conditions. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of metoclopramide, pertinent for interprofessional team members in treating patients with conditions that are of clinical value.

Objectives:

• Explain the mechanisms of action of metoclopramide.
• Identify the approved and off-label indications for metoclopramide.
• Review the potential adverse events associated with metoclopramide.
• Summarize the contraindications to therapy with metoclopramide.

Indications

The FDA has approved metoclopramide to treat nausea and vomiting in patients with gastroesophageal reflux disease (in patients who fail to respond to established therapy) and diabetic gastroparesis by increasing gastric motility.[1][2] Parenteral metoclopramide is also FDA approved to control nausea and vomiting in chemotherapy patients.[3][4]

Metoclopramide is used off-label prophylactically to prevent nausea and vomiting in postoperative patients when nasogastric suction is contraindicated or unavailable. It is particularly useful in this role because it does not cause any concomitant increase in gastric secretions.[5] Metoclopramide is also used off-label to treat acute migraine in the emergency department. It is an effective adjunctive agent for acute nausea and vomiting and reduces headache intensity; hence it is a valuable agent for the short-term treatment of acute migraine in the ED. It is important to recognize that FDA has not explicitly approved it for acute migraine. Still, it is a valuable alternative to opioids due to the potential for opioid use disorder.[6][7]

Metoclopramide can also be used off-label to treat hyperemesis gravidarum in pregnant patients; still, it should be used cautiously because of the lack of studies on the effects of the drug in pregnant women.[8][9] Recent studies have also shown evidence of metoclopramide’s efficacy in treating Diamond Blackfan syndrome.[10][11] Metoclopramide has also been efficacious in treating nausea in critically ill advanced liver disease patients.[12]

Mechanism of Action

Metoclopramide works by antagonizing central and peripheral dopamine-two receptors (D2) in the medullary chemoreceptor trigger zone in the area postrema, usually stimulated by levodopa or apomorphine. It achieves this by decreasing the sensitivity of visceral afferent nerves that transmit from the gastrointestinal system to the vomiting center in the area postrema in the chemoreceptor trigger zone.[13] In addition to antagonizing dopamine receptors, metoclopramide is an antagonist at 5HT3 (type 3 serotonin receptors) and an agonist at 5HT4 receptors.[14][15] Metoclopramide also blocks the antiperistaltic effects of apomorphine, allowing metoclopramide to slow apomorphine's inhibition of gastric emptying, thereby accelerating gastric emptying by increasing the amplitude and duration of esophageal contractions. Consequently, it increases the resting tone of the lower esophageal sphincter while simultaneously relaxing the duodenal bulb and pyloric sphincter, thereby increasing the peristalsis of the duodenum and jejunum.[16][17]

Pharmacokinetics

Absorption: Metoclopramide is rapidly and well absorbed from the gastrointestinal tract, and peak plasma concentrations are attained about 1 to 2 hours after the oral dose. Metoclopramide is lipid-soluble, giving it a large half-life and a large volume of distribution. Its half-life can range from 4.5 hours to 8.8 hours.[18]

Distribution: The volume of distribution is high (approximately 3.5 L/kg), which suggests the extensive distribution of drugs to the tissues.[19]

Metabolism: Metoclopramide is metabolized by oxidation primarily via cytochrome P450 2D6 (CYP2D6), glucuronide, and sulfate conjugation.[20]

Excretion: In a study, approximately 85% of the radioactivity of an orally administered dose is recovered in the urine, and half of it is present as a parent or conjugated metoclopramide. Around 18–22% of the dose is recovered as free metoclopramide in urine. Metoclopramide's elimination half-life in adults with normal renal function has been reported to be ~ 6 hours. In adults with severe renal impairment, there is a reduced metoclopramide clearance, increasing the elimination half-life (7.7 to 17.8 hours).[14]

Administration

Metoclopramide is generally administered orally in a tablet or solution form. The dosage of the tablets and solutions is generally 5 to 10 mg. It is usually taken before meals and before sleep. However, it can be administered intramuscularly or intravenously in severely nauseous patients; the intravenous route takes effect much more quickly.[13] Parenteral metoclopramide is also 5 mg. Rectal administration is also an option, as is an intraperitoneal injection in patients undergoing peritoneal dialysis.[21] The USFDA also approved metoclopramide nasal spray for symptomatic relief in adults with acute and recurrent diabetic gastroparesis. The nasal formulation has a unique benefit; it can be absorbed without depending on the absorption in the state of gastroparesis, thus ensuring the delivery of a therapeutic dose of metoclopramide.[22]

Metoclopramide dosing for various indications is as follows:

Diabetic Gastroparesis: 10 mg orally/IV/IM four times daily for a maximum duration of 12 weeks; max dose is 40 mg daily. Start at 5 mg four times daily for geriatric patients. For patients who are poor CYP2D6 metabolizers, give 5 mg four times daily (30 minutes before meals and at bedtime) with a max dose of 20 mg daily.[2]

GERD (chronic): 10 to 15 mg orally/IM/IV four times daily for a maximum duration of 12 weeks; maximum dose of 60 mg daily. Start at 5 mg four times daily for geriatric patients; max dose 30 mg daily. For patients who are poor CYP2D6 metabolizers, give 5 mg four times daily (30 minutes before meals and at bedtime) or 10 mg three times daily (30 minutes before meals).

GERD (intermittent): Up to 20 mg orally/IV/IM for one dose before symptoms begin.

Prophylaxis of Chemotherapy-related Nausea and Vomiting: 1 to 2 mg/kg/dose IV every 2 to 3 hours; the first dose is given 30 minutes before starting chemotherapy, then repeated for two doses every 2 hours, then three doses every 3 hours. Pretreat with diphenhydramine to reduce extrapyramidal symptoms. Metoclopramide is not a first-line agent for this purpose.

Use in Specific Patient Populations

Patients with Hepatic Impairment: Reduce the dose of metoclopramide in patients with moderate or severe hepatic impairment (Child-Pugh B or C). The recommended dose for diabetic gastroparesis is 5 mg four times daily.

Patients with Renal Impairment: In patients with kidney failure, it is generally recommended that metoclopramide maintenance doses be reduced to avoid drug accumulation.[23] Use caution in moderate or severe renal impairment (creatinine clearance<60 mL/minute). In patients with end-stage renal disease requiring hemodialysis, the maximum recommended dose is 5 mg twice daily. Lifestyle modification in the form of smaller and more frequent meals is first-line therapy. According to the American society of nephrology guidelines, metoclopramide can be used at 2.5 mg every four hours in refractory cases.[24]

Pregnancy Considerations: Metoclopramide can cross the placental barrier. Maternal administration of metoclopramide during delivery can lead to extrapyramidal signs and methemoglobinemia in neonates. According to ACOG(The American College of Obstetricians and Gynecologists) guidelines, metoclopramide should be used only in refractory cases of nausea and vomiting during pregnancy, 5 to 10 mg every 6 to 8 hours, orally or intramuscularly, in adequately hydrated patients. The preferred pharmacological management is pyridoxine(vitamin B6) or pyridoxine in combination with doxylamine.[25]

Breastfeeding Considerations: Metoclopramide is used as a galactagogue, but the clinical value of metoclopramide in increasing milk supply is uncertain. A meta-analysis of eight clinical trials indicated that metoclopramide increased serum prolactin but did not increase milk supply. Metoclopramide use increases the risk of postpartum depression and tardive dyskinesia. Use with caution.[26]

Adverse Effects

Adverse effects of metoclopramide use include extrapyramidal symptoms.[27][28] These include the following:

• Acute dystonic reactions
  • Torticollis
  • Trismus
  • Opisthotonus
  • Akathisia
  • Dystonia
  • Oculogyric crisis
  • Laryngospasm
  • Hyperprolactinemia
  • Tardive dyskinesia
  • Parkinson symptoms
  • Neuroleptic malignant syndrome 

Neuroleptic malignant syndrome is a rare adverse effect.[29] It is among the most serious adverse reactions because it manifests as follows:

• Hyperthermia
• Lead pipe rigidity
• Leukocytosis
• Elevated creatine phosphokinase levels
• Altered consciousness
• Symptoms of autonomic instability (potentially) 

• Diaphoresis
• Tachycardia
• Incontinence
• Pallor
• Irregular blood pressure or pulse
• Cardiac arrhythmias

Thus, any patient on metoclopramide who develops neuroleptic malignant syndrome should have metoclopramide immediately discontinued and undergo treatment with dantrolene. These adverse effects stem from metoclopramide’s anti-dopaminergic mechanism of action. It is important to note that these adverse effects are dose-independent and generally reversible following discontinuation of the drug.[30] Furthermore, it is important to keep in mind that oculogyric crises caused by metoclopramide can resemble the following:

• Seizures
• Cranial nerve palsies
• Paroxysmal tonic upward gaze
• Encephalopathy[31]

Metoclopramide-induced hyperprolactinemia can cause the following:

• Gynecomastia
• Galactorrhea
• Amenorrhea
• Impotence
• Hypogonadism

In patients with glucose-6-phosphate dehydrogenase deficiency or nicotinamide adenine dinucleotide cytochrome b5 reductase deficiency, metoclopramide can cause methemoglobinemia and sulfhemoglobinemia.[32][33] Additionally, metoclopramide can increase serum aldosterone levels, potentially causing fluid retention and volume overload. Therefore, it must be used with caution in patients with heart failure or cirrhosis of the liver.[34] Metoclopramide has also been shown to cause a non-thrombocytopenic purpuric rash that subsides upon discontinuation of the drug.[35]

Less acute adverse effects of metoclopramide, generally reversible and observed in children, include the following:

• Sedation 
• Diarrhea[36]

Rarer psychiatric side effects that have developed following brief exposure to metoclopramide include:

• Panic disorder
• Major depressive disorder
• Agoraphobia[37]

Drug-Drug Interactions

Reduced efficacy of dopamine agonists(like bromocriptine and cabergoline)[38] Furthermore, metoclopramide can increase serum aspirin levels by increasing the absorption of aspirin, potentially causing salicylate toxicity.[39] In addition to increasing the absorption of aspirin, metoclopramide can also increase serum levels of bupropion and its metabolite hydroxybupropion because it aids gastric emptying and thus bupropion absorption in the small intestine.[40] This can increase the serum levels of other drugs, given that bupropion and hydroxybupropion, in turn, inhibit the effects of the CYP2D6 metabolic enzyme.[41] 

Concurrent administration of metoclopramide and antipsychotic drugs should be avoided due to the potential for additive effects and neuroleptic malignant syndrome(NMS).[42] Metoclopramide should not be administered with CYP2D6 inhibitors like fluoxetine as there is an increased risk of extrapyramidal symptoms.[43]

Contraindications

Metoclopramide is contraindicated in patients with the following:

• Known hypersensitivity to metoclopramide or excipients[44]
• Gastrointestinal bleeding 
• Obstruction 
• Perforation[30]

Other contraindications include the following:

• Pheochromocytoma
• Seizures
• Depression
• Parkinson disease

Metoclopramide is contraindicated in patients with depression because it can cause major depressive disorder.[37] It is contraindicated in patients with seizures because it lowers the seizure threshold and can result in longer and more frequent seizures.[45] It is contraindicated in patients with depression and Parkinson disease because of the aforementioned adverse effects of major depressive disorder and parkinsonian symptoms. It is contraindicated in pheochromocytoma because it releases catecholamines and can exacerbate pheochromocytoma, causing a hypertensive crisis, which can be treated with phentolamine.[46][45]

US Boxed Warning: Metoclopramide can cause tardive dyskinesia, a serious movement disorder. Tardive dyskinesia risk increases with the total treatment duration and total cumulative exposure. Therefore, avoid treatment with metoclopramide tablets for longer than 12 weeks. Discontinue metoclopramide in patients who develop clinical signs or symptoms of tardive dyskinesia. In some patients, symptoms may decrease or resolve after metoclopramide is discontinued.[47][48]

Monitoring

It is also important to note that the efficacy of metoclopramide can be diminished if the patient takes anticholinergics or narcotic analgesic medications because these drugs decrease the gastric emptying rate.[49] Metoclopramide decreases the absorption rate of drugs generally absorbed from the stomach, like digoxin, while increasing the absorption of drugs absorbed from the small intestine, like cyclosporine.[50][51]

Metoclopramide is included in the KIDS list (Key Potentially Inappropriate Drugs in Pediatrics), a reference tool to identify medications associated with a high risk for adverse drug reactions. Monitor when metoclopramide is used in pediatric patients.[52] Metocloclopramide is also recognized as a potentially inappropriate medication for older adults per the American Geriatrics Society 2019 updated Beers criteria. Monitor elderly patients for extrapyramidal symptoms and tardive dyskinesia.[53]

Toxicity

The following are the primary symptoms of metoclopramide overdose:

• Sedation[54]
• Diarrhea[55]
• Extrapyramidal adverse effects (particularly tardive dyskinesia)[27]

Tardive dyskinesia is an adverse effect, often seen in antipsychotic medications, that generally manifests as grimacing, lip-smacking, tongue flicking, and general choreoathetoid movements of the body.[56] Because it can sometimes be irreversible, it is the most threatening potential complication of metoclopramide overdose, and metoclopramide treatment should be discontinued in any patient who develops tardive dyskinesia. Extrapyramidal adverse effects have been observed in metoclopramide overdose, particularly in infants and the elderly, who are at the most significant risk.[57] Retrospective analysis has shown that pediatric emergency room visits leading to extrapyramidal symptoms can be caused by metoclopramide syrup overdose.[58]

Though there is no specific treatment for metoclopramide overdose, its extrapyramidal effects are among the most common adverse effects. They can be alleviated with anticholinergics like benztropine and antihistamines like diphenhydramine.[59] Supportive therapy is recommended, while dialysis is generally ineffective in treating metoclopramide overdose.[23]

Enhancing Healthcare Team Outcomes

Metoclopramide is widely used in most hospitals and is an effective drug for gastroparesis and postoperative nausea and vomiting. However, the drug does have several side effects that all healthcare practitioners must be familiar with, so an interprofessional team approach is necessary. The nurse and pharmacist are in a prime position to monitor the drug and, hopefully, reduce its adverse effects by closely monitoring the patient and recommending discontinuation when symptoms arise. Of all the side effects, the most concerning are the extrapyramidal reactions that are more likely to occur in diabetics, children, seniors, and those already taking antipsychotic medications. The risk of developing tardive dyskinesia from metoclopramide varies from 1 to 15%, and the condition is quite debilitating. Hence, before using this drug, the nurse, pharmacist, and prescriber should obtain informed consent from the patient. All patients should be told about the potential for developing dyskinesias before treatment. If the patient has an adverse risk profile, the pharmacist should offer another agent option to the prescriber for consideration.

All interprofessional team members are also responsible for communicating concerns with other team members. They must also maintain accurate and updated records of their observations and interventions with the patient so that all team members have the most recent data on the case. Closely monitoring the patient is critical, and the interprofessional team, including clinicians, nursing, and pharmacy, will drive optimal outcomes.[60] [Level 5]

Outcomes

Metoclopramide has proven valuable in managing diabetic gastroparesis, postoperative nausea, and vomiting. However, the potential risk for dyskinesias has led to a re-evaluation of this agent. Experts indicate that metoclopramide should be started with the lowest possible dose and the shortest duration of time. The drug is effective in the short term, but its CNS adverse drug reactions are worrisome.[61] [Level 5]