Mechanism of Action Differences Between Promethazine and Domperidone
Promethazine and domperidone work through fundamentally different mechanisms: promethazine is primarily an H1-receptor antagonist with multiple central nervous system effects, while domperidone is a selective peripheral D2 dopamine receptor antagonist that does not cross the blood-brain barrier.
Primary Mechanisms of Action
Promethazine
Promethazine functions as a phenothiazine derivative with H1-receptor antagonism as its primary mechanism, competitively blocking histamine H1 receptors throughout the body including the central nervous system 1.
Dopaminergic blockade occurs centrally, as promethazine blocks postsynaptic dopaminergic receptors in the brain, contributing to its antiemetic properties 1, 2.
Strong alpha-adrenergic inhibitory effects contribute to both its sedative properties and risk of hypotension 1, 2.
Anticholinergic activity adds to its clinical effects and side effect profile, including dry mouth, urinary retention, and blurred vision 1, 2.
Domperidone
Domperidone is a selective D2 dopamine receptor antagonist that critically does NOT cross the blood-brain barrier, limiting its action to peripheral dopamine receptors 3, 4, 5.
Acts primarily on the chemoreceptor trigger zone (which lies outside the blood-brain barrier) and motor function of the stomach and small intestine 5.
Increases gastric emptying of liquids and increases lower esophageal sphincter pressure through its peripheral prokinetic effects 4.
No significant antihistaminic, anticholinergic, or alpha-adrenergic effects, making its mechanism far more selective than promethazine 3, 4.
Clinical Implications of Mechanism Differences
Central Nervous System Effects
Promethazine causes significant CNS depression and sedation due to its ability to cross the blood-brain barrier and affect central H1 and dopamine receptors 1.
Domperidone has minimal CNS penetration, resulting in virtually no sedation or central neurological effects 3, 4, 5.
Extrapyramidal side effects are common with promethazine (restlessness to oculogyric crises) due to central dopamine blockade 1, 2.
Domperidone has a much lower propensity for extrapyramidal effects because it does not readily enter the central nervous system 4, 5.
Pharmacokinetic Differences
Promethazine has rapid onset (5 minutes IV, 20 minutes oral) with duration of 4-6 hours and plasma half-life of 9-16 hours 1, 2, 6.
Domperidone undergoes rapid hepatic metabolism with terminal plasma half-life of approximately 6 hours and very low systemic bioavailability 3.
Promethazine is 91-93% protein bound with wide tissue distribution including the brain 6.
Domperidone is also 91-93% protein bound but has wide tissue distribution with specifically low brain concentration 3.
Safety Profile Differences
Promethazine Risks
Respiratory depression is a significant concern, particularly when combined with other CNS depressants like benzodiazepines and opioids 1, 2.
Severe tissue injury can occur with inadvertent perivascular extravasation, intra-arterial injection, or intraneuronal infiltration, including tissue necrosis and gangrene 1.
Neuroleptic malignant syndrome is a rare but serious complication 1, 2.
Domperidone Safety Advantages
Excellent safety profile for long-term administration without the neurological complications seen with promethazine 5.
Does not aggravate extrapyramidal side effects of neuroleptic drugs, unlike promethazine 4.
Side effects seldom occur with therapeutic doses, and when they do, they are typically mild and peripheral 4.
Clinical Applications Based on Mechanism
When Promethazine's Mechanism is Advantageous
Sedation is desired as an adjuvant effect for procedures or when treating nausea with insomnia 1, 7.
Multiple symptoms require treatment (nausea, allergic symptoms, sedation) due to its multi-receptor activity 2, 6.
When Domperidone's Mechanism is Preferred
Gastroparesis or delayed gastric emptying where prokinetic effects are needed 5.
Long-term antiemetic therapy where CNS side effects must be avoided 4, 5.
Patients on anti-Parkinsonian drugs (bromocriptine, levodopa) where domperidone can control peripheral nausea without worsening central symptoms 4.
Pediatric populations where extrapyramidal effects are particularly concerning 4.