Mechanism of Action
Domperidone belongs to the therapeutic class, anti-emetic, and is a “peripheral dopamine D2 and D3 receptor antagonist”. It reliefs the feeling of nausea and vomiting by acting on chemo-receptor trigger zone’s receptors and blocking them to inhibit nausea. The chemo-receptor trigger zone is principally responsible for mediating nausea present at the fourth ventricle near brain. It eventually elevates the upper gastrointestinal tract’s motility up to the restrained degree, and thus increasing the pressure of lower oesophageal sphincter through the blockage of dopamine receptors present in duodenum and gastric antrum. It mainly affects the anterior pituitary gland, particularly the dopamine receptors, and increases the prolactin release resulting in increased lactation. However, this drug is more beneficial in some patients, otherwise might induce adverse effects in other individuals either by means of genetic properties, for instance polymorphism in ABCB1 (a drug transporter gene) which is responsible for encoding of P-glycoprotein, an “α1D adrenoceptor ADRA1D gene”, and “voltage-gated potassium channel KCNH2 gene”.
Since it could not freely pass through the blood brain barrier, its anti-emetic effects are probably due to the mixture of antagonism of crucial dopamine receptors and gastrokinetic or peripheral effects present in the area postrema, specifically chemoreceptor trigger zone outside the blood brain barrier. Sometimes it also causes extra-pyramidal adverse effects, however, it does not affect the prolactin levels. Moreover, upon its systemic administration, it potentially antagonises the influence of dopamine more efficiently, as compared to the intracerebral administration. However, this drug has no remarkable effects on the gastric secretion.
This drug is rapidly absorbed after oral administration in fasting subjects, reaching the “peak plasma concentrations” at about 30 – 60 min. However, it shows a decrease in bioavailability of around 15% through oral route, possibly because of significant first pass metabolism in liver as well as the gut wall. Enhanced bioavailability of domperidone has been observed in normal individuals after taking the meal. The individuals presenting with GI complaints must take this drug at least half an hour before the meals. The oral bioavailability of domperidone is known to be decreased by preceding simultaneous administration of sodium bicarbonate along with cimetidine. As a result of which, the peak absorption time is delayed to some extent, whereas the area under the curve (AUC) is slightly increased by the oral administration of the drug after the meals.
The oral administration of this drug does not apparently induce or accumulate its own metabolism; rather a “peak plasma level” of 21 ng/mL is usually achieved after approximately after 90, followed by 30 mg per day oral administration for about two weeks. The peak plasma level after first dose is around18 ng/mL. The domperidone binds to the plasma proteins by 91 to 93%. It is widely distributed in the tissues; however shows lower concentrations in brain.
The domperidone is exclusively metabolised by hepatic metabolism by means of N-dealkylation and hydroxylation. The research on in vitro metabolism has stated 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”
The amounts of oral dose of domperidone in faecal as well as urinary excretions have been found to be approximately 66% and 31%, respectively. However, the amount of drug that remained unchanged is about 1% through urinary excretion and10% through faecal excretion. The plasma ½ life is 7-9 hours after single oral dose in healthy individuals with extensive renal deficiency.
Special Populations; Hepatic Impairment
The amount of domperidone in individuals presenting restrained liver impairment, for instance “Pugh score 7 to 9, Child-Pugh rating B”, whereas the area under curve and Cmax is found to be 2.9- and 1.5-fold higher when compared to the healthy persons. The terminal elimination ½ life has been enhanced by 15 to 23 hrs, whereas the uninhibited fraction is elevated by 25 per cent. The patient who represented mild hepatic impairment showed slightly lower systemic exposure as compared to the healthy individuals on the basis of area under curve and Cmax, without any apparent change in terminal half-life or protein binding.