Metoclopramide

Article Author:
Sasank Isola
Article Editor:
Ninos Adams
Updated:
10/1/2018 9:04:30 AM
PubMed Link:
Metoclopramide

Indications

Metoclopramide has been approved by the FDA specifically to treat nausea and vomiting in patients with gastroesophageal reflux disease or diabetic gastroparesis by increasing gastric motility[1],[2],[3]. It is also used to control nausea and vomiting in chemotherapy patients[4]. 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[5],[6]. It is particularly useful in this role because it does not cause any concomitant increase in gastric secretions[7]. Metoclopramide can also be used to treat hyperemesis gravidarum in pregnant patients, though 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]. Metoclopramide has also been efficacious in the treatment of nausea in advanced liver disease[11].

Mechanism of Action

Metoclopramide works by antagonizing central and peripheral dopamine two receptors in the medullary chemoreceptor trigger zone in the area postrema that are normally 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 [12]. Metoclopramide also blocks the antiperistaltic effects of apomorphine, which allows metoclopramide to slow apomorphine’s inhibition of gastric emptying, thereby accelerating gastric emptying by increasing the amplitude and duration of esophageal contractions. This also increases the resting tone of the lower esophageal sphincter while simultaneously relaxing the duodenal bulb and pyloric sphincter, thereby increasing peristalsis of the duodenum and jejunum[13]. In addition to antagonizing dopamine and apomorphine, metoclopramide also acts against type 3 serotonin receptors, though it has a weaker effect on these receptors than on the aforementioned dopamine and apomorphine receptors[14].

Administration

Metoclopramide is generally administered orally in 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, in severely nauseous patients, it can be administered intramuscularly or intravenously, with the latter route taking effect much more quickly[12]. Parenteral metoclopramide is also generally 5 mg. Rectal administration is also an option, as is an intraperitoneal injection in patients undergoing peritoneal dialysis[15]. In patients with kidney failure, it is generally recommended that maintenance doses of metoclopramide be reduced to avoid drug accumulation[16].

Adverse Effects

Adverse effects of metoclopramide use include extrapyramidal symptoms including the following:[17],[18],[19],[20],[21]

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

Though neuroleptic malignant syndrome is a rarer adverse effect, it is among the most serious, because it manifests as the following:[22]

  • 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.[23] Furthermore, it is important to keep in mind that oculogyric crises caused by metoclopramide can resemble the following:[24]

  • Seizures
  • Cranial nerve palsies
  • Paroxysmal tonic upward gaze
  • Encephalopathy

Metoclopramide-induced prolactinemia can cause the following:[25]

  • Gynecomastia
  • Galactorrhea
  • Amenorrhea
  • Impotence
  • Hypogonadism
  • Reduced efficacy of dopamine agonists (like bromocriptine and cabergoline)

Furthermore, metoclopramide can increase serum aspirin levels by increasing absorption of aspirin, potentially causing salicylate toxicity[26]. 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[27]. This can increase the serum levels of other drugs given that bupropion and hydroxybupropion, in turn, inhibit the effects of the CYP2D6 metabolic enzyme[28]. In patients with glucose 6 phosphate dehydrogenase deficiency or nicotinamide adenine dinucleotide cytochrome b5 reductase deficiency, metoclopramide can cause methemoglobinemia and/or sulfhemoglobinemia[29],[30]. Additionally, metoclopramide can increase serum aldosterone levels, potentially causing fluid retention and volume overload, and therefore must be used with caution in patients with heart failure or cirrhosis of the liver.[31] Metoclopramide has also been shown to cause a non-thrombocytopenic purpuric rash that subsides upon discontinuation of the drug.[32]

Less acute adverse effects of metoclopramide, generally reversible and observed in children include the following:[33]

  • Sedation 
  • Diarrhea 

Rarer psychiatric side effects that have developed following brief exposure to metoclopramide include:[34]

  • Panic Disorder
  • Major depressive disorder
  • Agoraphobia

Contraindications

Metoclopramide is contraindicated in patients with the following:[23]

  • Gastrointestinal Bleeding
  • Obstruction
  • Perforation

Other contraindications include the following:

  • Pheochromocytoma
  • Seizures
  • Depression
  • Parkinson disease
  • History of tardive dyskinesia

Metoclopramide is contraindicated in patients with depression because it can cause major depressive disorder[34]. It is contraindicated in patients with seizures because it lowers the seizure threshold and can result in longer and more frequent seizures[3]. It is contraindicated in patients with depression and Parkinson disease because of the aforementioned adverse effects of major depressive disorder and Parkinson symptoms. It is contraindicated in pheochromocytoma because it releases catecholamines, and therefore can exacerbate pheochromocytoma causing a hypertensive crisis, which can be treated with phentolamine.[35],[3]

Monitoring

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.[36]. It is also important to note that the efficacy of metoclopramide can be diminished if the patient is also taking anticholinergics or narcotic analgesic medications because these drugs decrease the rate of gastric emptying.[37] Metoclopramide decreases the rate of absorption of drugs which are generally absorbed from the stomach, like digoxin, while increasing the absorption of drugs absorbed from the small intestine, like cyclosporine.[38],[39]

Toxicity

The following are the primary symptoms of metoclopramide overdose:[40],[41],[19]

  • Sedation
  • Diarrhea
  • Extrapyramidal adverse effects (particularly tardive dyskinesia)

Tardive dyskinesia an adverse effect, often seen in antipsychotic medications, that generally manifests as grimacing, lip smacking, and tongue flicking as well as general choreoathetoid movements of the body[42]. 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 greatest risk[43]. Though there is no specific treatment for metoclopramide overdose, its extrapyramidal effects are among the most common adverse effects and can be ameliorated with anticholinergics like benztropine as well as antihistamines like diphenhydramine[44]. Supportive therapy is recommended, while dialysis is generally ineffective in treating metoclopramide overdose.[16]

Enhancing Healthcare Team Outcomes

Metoclopramide is widely used in most hospitals and it is an effective drug for gastroparesis and postoperative nausea and vomiting. However, the drug does have a number of side effects which all healthcare workers must be familiar with. The nurse and pharmacist are in a prime position to monitor the drug and hopefully reduce its adverse effects by close monitoring of the patient and recommending discontinuation when symptoms arise. Of all the side effects, the ones that are of most concern are the extrapyramidal reactions which are more likely to occur in diabetics, children, seniors and those who are already taking antipsychotic medications. The risk of developing tardive dyskinesia from this agent varies from 1 to 15%, and the condition is quite debilitating. Hence, prior to use of this drug, the nurse, pharmacist and physician should obtain an informed consent from the patient. All patients should be told about the potential for developing dyskinesias prior to treatment. If the patient has an adverse risk profile, then the pharmacist should offer another agent. In any case, close monitoring of the patient is key.[45] (Level V)

Outcomes

Metoclopramide has proven to be of value in the management of post-operative nausea and vomiting and diabetic gastropathy. 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 side effects are worrisome.[46] (Level V)