Metoclopramide

Mechanism

Mechanism of action

Metoclopramide acts through a multifactorial pharmacodynamic mechanism:

1. Dopamine Receptor Type 2 (D₂) Antagonism: At the peripheral level in the upper gastrointestinal tract, dopamine exerts a tonic inhibitory tone on the release of acetylcholine at the neuromuscular junctions of the myenteric plexus of Auerbach. By selectively blocking the D₂ receptor, metoclopramide reverses this dopaminergic inhibition by facilitating the local release of acetylcholine, which results in an increase in the tone of the lower esophageal sphincter (LES), an increase in the amplitude of antral contractions of the stomach and coordinated relaxation of the pyloric sphincter and duodenum.
2. Serotonin 5-HT₄ Receptor Agonism: Facilitates the presynaptic release of acetylcholine in a synergistic manner, coordinatingly enhancing gastric emptying of solids and liquids and accelerating transit in the proximal small intestine.
3. Central Blockade of D₂ and 5-HT₃ Receptors: In the Chemoreceptor Trigger Zone (ZGQ) of the brain area postrema and in the nucleus of the solitary tract. This central blockade is directly responsible for its powerful antiemetic therapeutic action.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and complete absorption after oral administration. Its systematic bioavailability varies from 60% to 80% due to moderate to variable first-pass hepatic metabolism.
• Distribution: High and hydrophilic volume of distribution (≈ 2.2 to 3.4 L/kg). It extensively crosses the blood-brain barrier and the human placental barrier. Low plasma protein binding (≈ 30%).
• Metabolism: Moderate hepatic through conjugation with sulfates and glucuronic acid. A minimal portion is metabolized by microsomal oxidation via CYP2D6.
• Excretion: Mainly renal. About 85% of the administered dose is recovered in the urine in the first 72 hours, 20% as free unchanged drug and the rest in the form of inactive metabolites.
• Half-life: 4 to 6 hours. It is significantly prolonged in patients with severe renal dysfunction.

Indicators and dose

Approved and Off-label indications

• Symptomatic treatment of acute and chronic relapsing diabetic gastroparesis acute and chronic recurrent.
• Prevention of nausea and vomiting postoperative and those induced by chemotherapy with low emetogenic potential.
• Adjunctive management of refractory GERD to improve esophagogastric motility.
• Facilitation of small bowel intubation and barium transit studies (Off-label/Diagnostic procedures).

Dosage and Clinical Adjustment

Adults:

• Diabetic gastroparesis: 10 mg orally, intravenously or intramuscularly three times daily, administered 30 minutes before main meals and at bedtime, for a maximum of 12 weeks.
• Prevention of highly emetogenic chemotherapy-induced nausea and vomiting: 1 to 2 mg/kg by slow intravenous administration every 2 hours for 2 to 5 doses.
• Standard 10 mg dosing is not advised in pediatric or elderly patients without close monitoring for extrapyramidal dyskinesias.

Adjustment in Kidney Failure:

• eGFR ≥ 50 mL/min: No adjustment required.
• eGFR 10 - 49 mL/min: Reduce the daily dose by 50%. Administer 5 mg three times daily.
• eGFR < 10 mL/min or hemodialysis: Reduce the daily dose to 25% - 50% or increase the interval between doses. Greater susceptibility to CNS adverse effects.

Adjustment in Liver Failure: No adjustment is required in mild to moderate impairment. In severe Child-Pugh C hepatic disease, a 50% dose reduction is recommended because overall metabolism is reduced.

Security

Risk of Extrapyramidal Effects and Tardive Dyskinesia (Black Box)

Due to its ability to easily cross the blood-brain barrier, metoclopramide nonspecifically blocks D₂ receptors in the cerebral striatum. This causes the appearance of acute extrapyramidal reactions (such as acute dystonias, oculogyric crises, lockjaw and spasmodic torticollis), especially in children, adolescents and young adults after initial doses. Likewise, its prolonged use for more than 12 weeks is associated with the development of reversible or irreversible tardive dyskinesia (involuntary movements of the tongue, face or extremities) in elderly female patients.

Contraindications

• Absolute: Known hypersensitivity to metoclopramide. Presence of active gastrointestinal bleeding, mechanical obstruction or intestinal perforation (the increase in intraluminal pressure induced by the prokinetic can cause rupture or dehiscence of sutures). Previous history of tardive dyskinesia due to neuroleptics. Suspected or confirmed diagnosis of pheochromocytoma (risk of severe hypertensive crises secondary to the induced release of catecholamines due to dopaminergic stimulation). Epilepsy (increases the frequency and severity of seizures).
• Relative: Moderate to severe renal failure. Parkinson's disease (dramatically worsens stiffness and tremor).

Adverse effects (ADRs)

Drug interactions

• Anticholinergic and Opioid Drugs: Anticholinergics (atropine) and opioid analgesics (morphine) exert an opposite pharmacodynamic effect on digestive motility. Its coadministration completely cancels the peripheral prokinetic effect of metoclopramide.
• By acceleration of gastric emptying: It notably increases the speed and absorption of multiple compounds such as paracetamol, acetylsalicylic acid, cyclosporine, diazepam and alcohol. Decreases the absorption of gastric digoxin.
• Strong CYP2D6 inhibitors: Concomitant use of fluoxetine, paroxetine, or bupropion may decrease metoclopramide clearance and exacerbate the incidence of extrapyramidal-type reactions.

Breastfeeding and Safety of Use

Metoclopramide is excreted in breast milk. Although concentrations are generally low, its ability to block central D₂ receptors can induce hyperprolactinemia in the mother and act secondarily as a galactogogue (stimulant of milk production). However, due to the risk of inducing severe extrapyramidal reactions and painful colic in the infant, its regular use is strongly discouraged during the period of active breastfeeding.