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Saturday, August 16, 2025

Metoclopramide


Executive overview

Metoclopramide is a prokinetic and antiemetic agent that acts as a dopamine D2 receptor antagonist with additional 5-HT3 receptor antagonism and 5-HT4 receptor agonism at higher doses. These combined actions make it effective in the management of nausea, vomiting, gastroparesis, gastroesophageal reflux, and certain radiological procedures requiring gastric emptying.

It is one of the most widely prescribed antiemetics but must be used with caution due to risks of extrapyramidal symptoms (EPS), tardive dyskinesia, and hyperprolactinemia with prolonged use. Most guidelines recommend short-term use only (≤5 days) in many settings.

Pharmacologic class and formulations

  • Class: Antiemetic, prokinetic, dopamine receptor antagonist

  • ATC code: A03FA01

  • Formulations:

    • Oral tablets (5 mg, 10 mg)

    • Oral solution (1 mg/mL, 5 mg/5 mL)

    • Intramuscular injection (10 mg/2 mL ampoule)

    • Intravenous injection (10 mg/2 mL ampoule; slow administration required)

    • Rectal suppositories (in some regions)

Mechanism of action

  • D2 receptor antagonism (central and peripheral):

    • At the chemoreceptor trigger zone (CTZ), reduces nausea and vomiting.

    • In the gastrointestinal tract, reduces inhibitory dopaminergic tone, enhancing gastric emptying.

  • 5-HT4 receptor agonism (enteric neurons):

    • Promotes acetylcholine release, enhancing peristalsis and coordination of gastric contractions.

  • 5-HT3 receptor antagonism (at higher doses):

    • Adds antiemetic benefit, particularly in chemotherapy-induced nausea and vomiting (CINV).

Effects:

  • Increased lower esophageal sphincter tone

  • Enhanced gastric emptying

  • Reduced nausea and vomiting

Pharmacokinetics

  • Absorption: Rapid oral absorption; bioavailability ~80%.

  • Distribution: Crosses blood–brain barrier and placenta; small amounts in breast milk.

  • Metabolism: Hepatic (glucuronidation, sulfation, oxidation).

  • Elimination: Primarily renal (as unchanged drug and metabolites).

  • Half-life: 5–6 hours (prolonged in renal impairment).

Clinical indications

Regulatory indications vary by country, but common uses include:

  1. Prevention and treatment of nausea and vomiting

    • Postoperative, migraine-related, or drug-induced (excluding long-term CINV prophylaxis, where newer agents are preferred).

  2. Diabetic gastroparesis (short-term use only).

  3. Facilitation of gastric emptying in radiological or endoscopic procedures.

  4. Migraine-associated nausea and vomiting (often used with analgesics).

  5. Chemotherapy-induced nausea and vomiting (CINV) (less common now; reserved for refractory cases due to EPS risk).

Contraindications

  • Pheochromocytoma (risk of hypertensive crisis)

  • History of tardive dyskinesia or drug-induced movement disorder

  • Gastrointestinal hemorrhage, obstruction, or perforation (risk of worsening condition)

  • Epilepsy (lowers seizure threshold)

  • Hypersensitivity to metoclopramide or components

  • Combination with levodopa or dopamine agonists (mutual antagonism)

Precautions

  • Duration of use: Avoid prolonged therapy (>5 days) due to risk of tardive dyskinesia.

  • Extrapyramidal side effects: Especially in children and young adults; avoid routine use in pediatrics unless essential.

  • Renal impairment: Accumulation can increase adverse effects; dose adjustment required.

  • Hepatic impairment: Clearance reduced; use cautiously.

  • Elderly: Higher risk of EPS, sedation, and tardive dyskinesia.

  • Pregnancy: Considered relatively safe (commonly used in hyperemesis gravidarum).

  • Breastfeeding: Excreted in small amounts; may stimulate prolactin secretion.

Adverse effects

Common

  • Drowsiness, fatigue

  • Diarrhea

  • Restlessness, agitation

Neurological (dose- and duration-dependent)

  • Acute dystonic reactions (oculogyric crisis, torticollis, opisthotonus) – more common in children/young adults

  • Akathisia, Parkinsonian symptoms

  • Tardive dyskinesia (potentially irreversible, especially in elderly women with prolonged use)

Endocrine

  • Hyperprolactinemia → galactorrhea, menstrual irregularities, gynecomastia

Rare but serious

  • Neuroleptic malignant syndrome (NMS)

  • Severe allergic reactions

Drug interactions

  • Levodopa, dopamine agonists: Antagonized by metoclopramide.

  • CNS depressants (alcohol, sedatives): Additive sedation.

  • Antipsychotics: Additive risk of EPS and tardive dyskinesia.

  • Serotonergic drugs (SSRIs, MAOIs, tramadol): Risk of serotonin syndrome.

  • Digoxin: Reduced absorption due to accelerated gastric emptying.

  • Ciclosporin: Increased absorption → risk of toxicity.

Dosage

Adults

  • Nausea and vomiting (general use):

    • Oral/IM/slow IV: 10 mg up to three times daily (max 30 mg/day).

    • Duration: Usually ≤5 days.

  • Diabetic gastroparesis (short-term):

    • 10 mg up to four times daily, 30 min before meals and at bedtime.

    • Max 40 mg/day.

  • Chemotherapy-induced nausea and vomiting (CINV; high doses):

    • 1–2 mg/kg IV (max 10 mg/dose in many guidelines) every 2–3 hours, often with diphenhydramine to reduce EPS risk.

    • Now largely replaced by 5-HT3 antagonists and NK1 antagonists.

Elderly

  • Use lowest effective dose; max 30 mg/day.

Children and adolescents

  • Restricted due to risk of neurological side effects.

  • Age 1–18 years (if no alternative available): 0.1–0.15 mg/kg up to three times daily (max 0.5 mg/kg/day; max 10 mg/dose).

  • Not recommended <1 year old.

Renal impairment

  • CrCl 30–60 mL/min: 50% of normal dose.

  • CrCl <30 mL/min: 25% of normal dose.

Clinical efficacy

  • Effective for acute nausea/vomiting from various causes, but limited by side effects with longer use.

  • Comparable to other dopamine antagonists (e.g., prochlorperazine) but higher risk of acute dystonia in young patients.

  • Still used in diabetic gastroparesis when other options (e.g., erythromycin, domperidone) are unsuitable.

  • CINV: largely replaced by safer, more effective regimens, but retains a role in refractory cases.

Patient counseling points

  • Take before meals when used for gastric motility.

  • May cause drowsiness — avoid driving or operating machinery until response is known.

  • Report involuntary movements, muscle spasms, or abnormal eye movements immediately.

  • Avoid alcohol and sedatives.

  • Limit use to the shortest duration possible.

  • Inform clinicians if on levodopa, dopamine agonists, or antidepressants.




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