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| Clinical data | |
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| Trade names | Phenergan, others[1] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682284 |
| License data | |
| Pregnancy category |
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| Dependence liability | Low[2] |
| Addiction liability | None-Very low[3] |
| Routes of administration | By mouth,rectal,intravenous,intramuscular,topical |
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| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability[4] |
| Protein binding | 93%[5] |
| Metabolism | Liverglucuronidation andsulfoxidation |
| Metabolites | Promethazine Sulphoxide, Desmethylpromethazine, Promethazine Hydroxy[6] |
| Eliminationhalf-life | 10–19 hours[4][7] |
| Duration of action | 4-6h (sometimes up to 12h)[8] |
| Excretion | Kidney andBile duct |
| Identifiers | |
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| CAS Number | |
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| IUPHAR/BPS | |
| DrugBank |
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| ChemSpider |
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| KEGG |
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| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.445 |
| Chemical and physical data | |
| Formula | C17H20N2S |
| Molar mass | 284.42 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
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Promethazine, sold under the brand namePhenergan among others, is afirst-generation antihistamine,sedative, andantiemetic used to treatallergies,nausea, and vomiting. It may also help with some symptoms associated with thecommon cold[9] and may also be used forsedating people who are agitated or anxious, an effect that has led to somerecreational use (especially with codeine).[10][11][12] Promethazine is takenby mouth (oral), as arectal suppository, or byinjection into a muscle (IM).[9]
Common side effects of promethazine include confusion and sleepiness;[9] consumption ofalcohol or other sedatives can make these symptoms worse.[9] It is unclear if use of promethazine duringpregnancy orbreastfeeding is safe.[9][11] Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing.[9] Use of promethazine by injection into a vein is not recommended, due to potential skin damage.[9] Promethazine is in thephenothiazine family of medications.[9] It is also a stronganticholinergic and at high or toxic doses can act as adeliriant.[13]
Promethazine was made in the 1940s by a team of scientists fromRhône-Poulenc laboratories.[14] It was approved for medical use in the United States in 1951.[9] It is ageneric medication and is available under many brand names globally.[1] In 2023, it was the 230th most commonly prescribed medication in the United States, with more than 1 million prescriptions;[15][16] and the combination withdextromethorphan was the 252nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[17][18]
Promethazine has a variety of medical uses, including:
Some documentedside effects include:
Less frequent:
Rare side effects include:
Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.[27] In many countries (including the US and UK), promethazine is contraindicated in children less than two years of age, and strongly cautioned against in children between two and six, due to problems with respiratory depression and sleep apnea.[28]
Promethazine is listed as one of the drugs with the highest anticholinergic activity in a study of anticholinergic burden, including long-term cognitive impairment.[29]
Promethazine inoverdose can produce signs and symptoms includingCNS depression,hypotension,respiratory depression,unconsciousness, and sudden death.[30] Other reactions may includehyperreflexia,hypertonia,ataxia,athetosis, andextensor-plantar reflexes.[30] Atypically and/or rarely,stimulation,convulsions, hyperexcitability, andnightmares may occur.[30]Anticholinergic effects likedry mouth,dilated pupils,flushing,gastrointestinal symptoms, anddelirium may occur as well.[30] Treatment of overdose is supportive and based on symptoms.[30]
Promethazine, a phenothiazine derivative, is structurally different from theneuroleptic phenothiazines, with similar but different effects.[4] Despite structural differences, promethazine exhibits a strikingly similar binding profile topromazine,[31] another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.[32] However, dosages used therapeutically, such as for sedation, have no antipsychotic effect.[33] It acts primarily as a strongantagonist of theH1 receptor (antihistamine,Ki = 1.4 nM[34]) and a moderatemACh receptor antagonist (anticholinergic),[4] and also has weak to moderateaffinity for the5-HT2A,[35]5-HT2C,[35]D2,[36][37] andα1-adrenergic receptors,[38] where it acts as an antagonist at all sites, as well. New studies have shown that promethazine acts as a strong non-competitive selectiveNMDA receptorantagonist, with an EC50 of 20 μM;[39] which might promote sedation in addition with the strongantihistaminergic effects of theH1 receptor, but also as a weakeranalgesic. It does not, however, affect theAMPA receptors.[39]
Another notable use of promethazine is as alocal anesthetic, by blockage ofsodium channels.[38]
| receptor | Ki (nM) | ref |
|---|---|---|
| α1A-adrenoceptor (Rat) | 32 | [40] |
| α1B-adrenoceptor (Rat) | 21 | [40] |
| α1D-adrenoceptor (Human) | 90 | [40] |
| α2A-adrenoceptor (Human) | 256 | [40] |
| α2B-adrenoceptor (Human) | 24 | [40] |
| α2C-adrenoceptor (Human) | 353 | [40] |
| Calmodulin (Human) | 60000 | [41][40][42] |
| Calmodulin (Bovine) | 50000 | [41][42][40] |
| Chloroquine resistance transporter (Plasmodium falciparum) | 85000 | [43][40] |
| D1 receptor (Human) | 1372 | [40] |
| D2 receptor (Human) | 260 | [40] |
| D3 receptor (Human) | 190 | [40] |
| H1 receptor (Human) | 0.33[40]-1.4[44] | [44][40] |
| H2 receptor (Human) | 1146 | [40] |
| M1 receptor (Human) | 3.32 | [40] |
| M2 receptor (Human) | 12 | [40] |
| M3 receptor (Human) | 4.15 | [40] |
| M4 receptor (Human) | 1.06 | [40] |
| M5 receptor (Human) | 3.31 | [40] |
| NET (Norephinephrine transporter) (Human) | 4203 | [40] |
| Prion protein (Human) | 8000 | [45][40] |
| 5-HT1A receptor (Rat) | 1484 | [40] |
| 5-HT2A receptor (Human) | 19 | [40] |
| 5-HT2B receptor (Human) | 43 | [40] |
| 5-HT2C receptor (Human) | 6.48 | [40] |
| 5-HT6 receptor (Human) | 1128 | [40] |
| SERT (Serotonin transporter) (Human) | 2130 | [40] |
| Sigma1 receptor (Human) | 120 | [40] |
| OCT1 (Human) | 35100 | [46][40] |
Solid promethazinehydrochloride is a white to faint-yellow, practically odorless, crystalline powder. Slow oxidation may occur upon prolonged exposure to air, usually causing blue discoloration. Itshydrochloridesalt is freely soluble in water and somewhat soluble in alcohol. Promethazine is achiral compound, occurring as a mixture ofenantiomers.[47]
Promethazine was first synthesized by a group atRhone-Poulenc (which later became part ofSanofi) led by Paul Charpentier in the 1940s.[48] The team was seeking to improve ondiphenhydramine; the same line of medical chemistry led to the creation ofchlorpromazine.[49]
As of July 2017, it is marketed under many brand names worldwide: Allersoothe, Antiallersin, Anvomin, Atosil, Avomine, Closin N, Codopalm, Diphergan, Farganesse, Fenazil, Fenergan, Fenezal, Frinova, Hiberna, Histabil, Histaloc, Histantil, Histazin, Histazine, Histerzin, Lenazine, Lergigan, Nufapreg, Otosil, Pamergan, Pharmaniaga, Phenadoz, Phenerex, Phenergan, Phénergan, Pipolphen, Polfergan, Proazamine, Progene, Prohist, Promet, Prometal, Prometazin, Prometazina, Promethazin, Prométhazine, Promethazinum, Promethegan, Promezin, Proneurin, Prothazin, Prothiazine, Prozin, Pyrethia, Quitazine, Reactifargan, Receptozine, Romergan, Sominex, Sylomet, Xepagan, Zinmet, and Zoralix.[1]
It is also marketed in manycombination drug formulations:
The recreational druglean, also known as purple drank among other names, consists of promethazine syrup mixed withSprite and either anopiate oropioid.[10]
In 2009, theUS Supreme Court ruled on aproduct liability case involving promethazine. Diana Levine, a woman with a migraine, was administeredWyeth's Phenergan viaIV push. The drug was injected improperly, resulting ingangrene and subsequent amputation of her right forearm below the elbow. A state jury awarded her $6 million inpunitive damages.
The case was appealed to the Supreme Court on grounds offederal preemption andsubstantive due process.[50] The Supreme Court upheld the lower courts' rulings, stating that "Wyeth could have unilaterally added a stronger warning about IV-push administration" without acting in opposition to federal law.[51] In effect, this means drug manufacturers can be held liable for injuries if warnings of potential adverse effects, approved by theUS Food and Drug Administration (FDA), are deemed insufficient by state courts.
In September 2009, the FDA required aboxed warning be put on promethazine for injection, stating the contraindication for subcutaneous administration. The preferred administrative route is intramuscular, which reduces the risk of surrounding muscle and tissue damage.[52]
This article incorporates text available under theCC BY 4.0 license.
