Promethazine

🧬 Receptor activity

Target	Action	Affinity	Source
Histamine H1 receptor	—	Ki 0.334 nM	CHEMBL
Muscarinic acetylcholine receptor M4	—	Ki 1.057 nM	CHEMBL
Muscarinic acetylcholine receptor M5	—	Ki 3.307 nM	CHEMBL
Muscarinic acetylcholine receptor M1	—	Ki 3.321 nM	CHEMBL
Muscarinic acetylcholine receptor M3	—	Ki 4.149 nM	CHEMBL
5-hydroxytryptamine receptor 2C	—	Ki 6.477 nM	CHEMBL
Muscarinic acetylcholine receptor M2	—	Ki 12 nM	CHEMBL
5-hydroxytryptamine receptor 2A	—	Ki 19 nM	CHEMBL
Alpha-1B adrenergic receptor	—	Ki 21 nM	CHEMBL
Alpha-2B adrenergic receptor	—	Ki 24 nM	CHEMBL
Alpha-1A adrenergic receptor	—	Ki 32 nM	CHEMBL
5-hydroxytryptamine receptor 2B	—	Ki 43 nM	CHEMBL
Alpha-1D adrenergic receptor	—	Ki 90 nM	CHEMBL
Sigma non-opioid intracellular receptor 1	—	Ki 120 nM	CHEMBL
D(3) dopamine receptor	—	Ki 190 nM	CHEMBL
Alpha-2A adrenergic receptor	—	Ki 256 nM	CHEMBL
D(2) dopamine receptor	—	Ki 260 nM	CHEMBL
Alpha-2C adrenergic receptor	—	Ki 353 nM	CHEMBL
Unchecked	—	Ki 842 nM	CHEMBL
5-hydroxytryptamine receptor 6	—	Ki 1128 nM	CHEMBL
Histamine H2 receptor	—	Ki 1146 nM	CHEMBL
D(1A) dopamine receptor	—	Ki 1372 nM	CHEMBL
5-hydroxytryptamine receptor 1A	—	Ki 1484 nM	CHEMBL
Sodium-dependent serotonin transporter	—	Ki 2130 nM	CHEMBL
Sodium-dependent noradrenaline transporter	—	Ki 4203 nM	CHEMBL
Trypanothione reductase	—	Ki 216000 nM	CHEMBL

Mechanism of action

Promethazine is a an antagonist of histamine H1, post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. The antihistamine action is used to treat allergic reactions. Antagonism of muscarinic and NMDA receptors contribute to its use as a sleep aid, as well as for anxiety and tension. Antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center make promethazine useful in the treatment of nausea and vomiting.
Promethazine is a phenothiazine derivative with potent sedative properties. Although the drug can produce either CNS stimulation or CNS depression, CNS depression manifested by sedation is more common with therapeutic doses of promethazine. The precise mechanism of the CNS effects of the drug is not known.
Although it has been reported that the drug has slight antitussive activity, this may result from its anticholinergic and CNS depressant effects. In therapeutic doses, promethazine appears to have no substantial effect on the cardiovascular system. Although rapid IV administration of promethazine may produce a transient fall in blood pressure, blood pressure usually is maintained or slightly elevated when the drug is given slowly.
Promethazine hydrochloride is a phenothiazine derivative which possesses antihistaminic, sedative, antimotion-sickness, antiemetic, and anticholinergic effects. Promethazine is a competitive H1 receptor antagonist, but does not block the release of histamine. Structural differences from the neuroleptic phenothiazines result in its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties.
The development of phenothiazine derivatives as psychopharmacologic agents resulted from the observation that certain phenothiazine antihistaminic compounds produced sedation. In an attempt to enhance the sedative effects of these drugs, promethazine and chlorpromazine were synthesized. Chlorpromazine is the pharmacologic prototype of the phenothiazines. The pharmacology of phenothiazines is complex, and because of their actions on the central and autonomic nervous systems, the drugs affect many different sites in the body. Although the actions of the various phenothiazines are generally similar, these drugs differ both quantitatively and qualitatively in the extent to which they produce specific pharmacologic effects. /Phenothiazine General Statement/
For more Mechanism of Action (Complete) data for Promethazine (18 total), please visit the HSDB record page.

Pharmacodynamics

Promethazine is is a histamine H1 antagonist that can be used for it's ability to induce sedation, reduce pain, and treat allergic reactions. Promethazine's effects generally last 4-6h but can last up to 12h. Patients should be counselled regarding CNS and respiratory depression, reduce seizure threshold, and bone marrow depression.

Pharmacokinetics

Half-life

The elimination half life of promethazine is approximately 12-15h.
Following intravenous administration in healthy volunteers, the plasma half-life for promethazine has been reported to range from 9 to 16 hours. The mean plasma half-life for promethazine after intramuscular administration in healthy volunteers has been reported to be 9.8 +/- 3.4 hours.
Half-life: 12 hours

Absorption

A 25mg dose of intramuscular promethazine reaches a Cmax of 22ng/mL. Intravenous promethazine reaches a Cmax of 10.0ng/mL, with a Tmax of 4-10h, and an AUC of 14,466ng\*h/mL. Oral promethazine is only 25% bioavailable due to first pass metabolism. Oral promethazine reaches a Cmax of 2.4-18.0ng/mL, with a Tmax of 1.5-3h, and an AUC of 11,511ng\*h/mL.
An intravenous dose of promethazine is 0.64% eliminated in the urine as the unchanged parent drug, 0.02-2.02% in the urine as desmethylpromethazine, 10% in the urine as promethazine sulfoxide.
The volume of distribution of promethazine is approximately 970L or 30L/kg.
The intravenous clearance of promethazine is approximately 1.14L/min. The renal clearance of promethazine is 5.9mL/min and the renal clearance of promethazine sulfoxide is 90.4mL/min.
Promethazine is well absorbed from the GI tract and from parenteral sites. Plasma concentrations of promethazine required for sedative effects are unknown. The onset of sedative effects occurs within 20 minutes following oral, rectal, or IM administration, and within 3-5 minutes following IV administration. The duration of sedative effects varies but may range from 2-8 hours depending on the dose and route of administration.
Promethazine is widely distributed in body tissues. Compared with other organs, lower concentrations of the drug are found in the brain, but this concentration is higher than the plasma concentration.

Metabolism

Promethazine is predominantly metabolized to promethazine sulfoxide, and minorly to desmethylpromethazine and a hydroxy metabolite. Hydroxylation of promethazine is predominantly mediated by CYP2D6.
Promethazine hydrochloride is metabolized in the liver, with the sulfoxides of promethazine and N-desmethylpromethazine being the predominant metabolites appearing in the urine.
Most metabolites of phenothiazines are pharmacologically inactive; however, certain metabolites (eg, 7-hydroxychlorpromazine, mesoridazine) show moderate pharmacologic activity and may contribute to the action of the drugs. There is limited evidence to indicate that some phenothiazines (eg, chlorpromazine) may induce their own metabolism. /Phenothiazine General Statement/
First order kinetics observed for oxidation of promethazine HCl in aqueous solution. Reaction rate was pH dependent up to pH 5. Cu ions increased rates as did Fe. Under anaerobic conditions, Cu and Fe were required for the reaction. Isolation of products carried out by tlc.
Incubation of promethazine (Ia) and desmethylpromethazine (Ib) with 9000g supernatant fractions of rabbit liver homogenate resulted in formation of N-dealkylated, N-oxygenated and ring-hydroxylated products. The N-oxidation products identified by t.l.c. and mass spectra using synthetic reference products are promethazine-N-oxide (IX) and the nitrone (VIII), which is believed to be formed chemically and metabolically from the metabolite N-hydroxydesmethylpromethazine (VII).
To determine which cytochrome P450 form is involved in the promethazine [10-(2-dimethylaminopropyl) phenothiazine] metabolism, in vitro analysis using human liver microsomes were performed. Promethazine was mainly biotransformed to ring-hydroxylated, S-oxidized and N-demethylated metabolites. The promethazine hydroxylase in human liver microsomes was inhibited by SKF-525A, propranolol, sparteine, quinidine and anti-CYP2D6 serum suggesting involvement of a P450 related to CYP2D6. Lineweaver-Burk plots for the hydroxylation, S-oxidation and N-demethylation indicated that the hydroxylation occurred with a low K(m) value in human liver microsomes. Microsomes from genetically-engineered human B-lymphoblastoid cells expressing CYP2D6 hydroxylated promethazine most efficiently as compared to other P450 forms, indicating that it was the principal P450 responsible for the metabolism of promethazine in human liver microsomes. The inhibition of CYP2D6-catalysed bufuralol 1'-hydroxylase by various histamine H3 antagonists including promethazine suggested that promethazine and some other histamine H1 antagonists could be inhibitors of this P450 in human liver microsomes.

Protein binding

Promethazine is 93% protein bound in serum, mostly to albumin.