Domperidone and Cinitapride

Mechanism

🩺 Domperidone

• Class: Pure antagonist of dopamine D₂ receptors.
• Safety Mechanism: Bulky and hydrophobic chemical structure that does not appreciably cross the blood-brain barrier in standard doses.
• Extrapyramidal effects: Extremely rare. However, it lacks a barrier on the pituitary gland (which resides outside the BBB), and can induce hyperprolactinemia.

🧬 Cinitapride

• Class: Potent and selective serotonin 5-HT₄ receptor agonist and dopamine D₂ receptor antagonist.
• Mechanism of Action: Facilitates the motility of the entire upper gastrointestinal tract in a coordinated manner, promoting gastric emptying and reducing gastroesophageal reflux optimally through the serotonergic pathway.

Mechanism of action

Domperidone: Competitively blocks the peripheral dopamine D₂ receptor. It increases the duration of antral and duodenal contractions, improves pyloroduodenal coordination and prevents delayed gastric emptying of dopaminergic origin. It lacks activity on serotonin receptors. Its antiemetic effect is mediated solely by the blockade of D₂ receptors located in the area postrema (central area devoid of an effective blood-brain barrier).

Cinitapride: Its main route of action is selective agonism of the 5-HT₄ receptor at the level of the enteric nervous system. Promotes the stimulation of neuronal adenylate cyclase and increases the synthesis of intracellular cAMP. This molecular change directly stimulates the massive release of acetylcholine at the gastrointestinal neuromuscular junction, increasing contractile force. At the same time, it exerts a moderate blockade of peripheral and central D₂ dopamine receptors.

Pharmacokinetics

Pharmacokinetics

Indicators and dose

Approved indications

• Domperidone: Exclusive relief of the symptoms of nausea and vomiting in adults and children over 12 years of age with a body weight greater than 35 kg. Symptomatic treatment of gastroparesis.
• Cinitapride: Symptomatic treatment of functional dyspepsia of the dysmotility type and adjuvant in the short-term treatment of refractory GERD.

Dosage and Clinical Adjustment

Adults:

• Domperidone: 10 mg orally three times a day, ideally administered 15-30 minutes before main meals. Maximum recommended daily dose: 30 mg. Limit use to a maximum of 7 continuous days.
• Cinitapride: 1 mg orally three times a day, administered 15 minutes before main meals.

Kidney and Hepatic Adjustment:

• Domperidone: Contraindicated in moderate to severe liver failure. In severe renal failure (eGFR < 30 mL/min), prolong the administration interval to a maximum of one or two daily doses.
• Cinitapride: Does not require adjustments in mild hepatic or renal failure. In severe deficiency, it is advisable to reduce the dose by 50% as a precaution.

Security

Cardiotoxicity and QT Prolongation Alert (Domperidone)

At high doses or in combination with CYP3A4 enzyme inhibitor drugs, domperidone exerts a direct blockade of the cardiac rectifier potassium channel hERG. This drastically prolongs myocardial repolarization and promotes the appearance on the electrocardiogram of a prolonged corrected QT interval (QTc), increasing the risk of potentially fatal ventricular arrhythmias such as Torsades de Pointes. Its use is strictly restricted to low doses and periods of less than one week, and it is contraindicated in subjects with underlying structural heart disease.

Contraindications

• Domperidone (Absolutes): Patients with known prolongation of the QTc conduction interval (or history), severe congestive heart failure, notable pre-existing electrolyte disorders (hypokalemia, hypomagnesemia), moderate or severe hepatic impairment (Child-Pugh B/C). Concomitant coadministration of strong CYP3A4 inhibitors (ketoconazole, erythromycin, clarithromycin, ritonavir).
• Cinitapride (Absolutas): Obstruction, perforation or active gastrointestinal bleeding.

Adverse effects (ADRs)

• Domperidone: Dry mouth, mild anxiety, headache. Transient gynecological manifestations due to elevated prolactin (galactorrhea, amenorrhea, breast sensitivity). Serious ventricular arrhythmias associated with overdose or interactions.
• Cinitapride: Mild fatigue, drowsiness. Dermal hypersensitivity reactions. Occasionally, mild transient dyskinesias in elderly patients with prolonged use.

Drug interactions

• Domperidone Interactions (Criticisms): The combined use of domperidone with potent inhibitors of the CYP3A4 enzyme increases the half-life and increases the maximum plasma concentrations of the drug up to 3 times, exacerbating hERG blockade and cardiotoxicity. Contraindicated combinations: Clarithromycin, erythromycin, itraconazole, ketoconazole, fluconazole, amiodarone, diltiazem, verapamil.
• Cinitapride: Its combination with QT prolonging drugs or strong CYP3A4 inhibitors requires close monitoring and periodic ECG control.

Breastfeeding and Pregnancy

Pregnancy: Limited data. The use of domperidone and cinitapride during pregnancy is not recommended unless there are no safe therapeutic alternatives available.

Breastfeeding (Domperidone): Compatible with caution. It is excreted in breast milk at minimal levels (RID ≈ 0.1%). However, due to the deleterious cardiotoxic effects of the drug, the infant should be closely monitored for any signs of cardiac disturbance or lethargy.