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Pharmacologic classification: Gastrokinetic (Prokinetic): Domperidone is a dopamine receptor antagonist used as a peristaltic stimulant and anti-emetic agent for dyspepsia, indigestion, epigastric pain, nausea, and vomiting.
Pharmacology: Pharmacodynamics: Domperidone is a dopamine receptor (D2) antagonist.
Domperidone is a selective peripheral dopamine antagonist at the D2 dopamine receptor in the Chemo-receptor Trigger Zone (CTZ) and stomach. Domperidone does not readily enter the central nervous system (the chemoreceptor trigger zone is considered to lie outside the blood-brain barrier). Domperidone increases spontaneous gastric activity and antagonizes dopamine inhibition of gastric emptying. Domperidone has been shown to increase lower esophageal sphincter pressure and promotes esophageal and antral peristalsis and also increases pyloric dilatation. Domperidone increases the frequency, amplitude, and duration of duodenal contraction and reduces the small bowel transit time. Domperidone has no acetylcholine-like effect.
Pharmacokinetics: Absorption: In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentration at 30 to 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to extensive first-pass metabolism in the gut wall and liver. Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastro-intestinal complaints should take domperidone 15-30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.
Distribution: Oral domperidone does not appear to accumulate or induce on its own metabolism; a peak plasma level after 90 minutes of 21 ng/mL after two weeks of oral administration of 30 mg per day was almost the same as that of 18 ng/mL after the first dose. Domperidone is 91-93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats.
Metabolism: Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation.
Excretion: Urinary and fecal excretions amount to 31 and 66% of the oral dose respectively. The proportion of the drug excreted unchanged is small (10% of fecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.
