|Oral, rectal, IV, IM, topical|
|Bioavailability||88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability|
|Metabolism||Hepatic glucuronidation and sulfoxidation|
|Biological half-life||16–19 hours|
|Excretion||Renal and biliary|
|Chemical and physical data|
|Molar mass||284.42 g/mol|
|3D model (JSmol)|
Promethazine is a neuroleptic medication and first-generation antihistamine of the phenothiazine family. The drug has strong sedative and weak antipsychotic effects. It also reduces motion sickness and has antiemetic (via its action on the dopamine receptor D2) and anticholinergic properties. In some countries it is prescribed for insomnia when benzodiazepines are contraindicated. It is available in many countries under many brand names. Promethazine was developed in the mid 1940s when a team of scientists from Rhône-Poulenc laboratories were able to synthesize it from phenothiazine and a diamine side chain of diphenhydramine.
- As a sedative
- For preoperative sedation and to counteract postnarcotic nausea
- To reduce nervousness, restlessness and agitation caused by psychiatric conditions (used for this purpose mainly in Europe)
- As antiallergic medication to combat hay fever (allergic rhinitis), etc., or to treat allergic reactions, alone or in combination with oral decongestants such as pseudoephedrine
- As an adjunct treatment for anaphylactoid conditions (IM/IV route preferred)
- Together with codeine or dextromethorphan against cough
- As a motion sickness or seasickness remedy when used with ephedrine or pseudoephedrine
- To combat moderate to severe morning sickness and hyperemesis gravidarum: In the UK, promethazine is drug of first choice, being preferred as an older drug with which there is a greater experience of use in pregnancy (second in line being metoclopramide or prochlorperazine).
- Previously, it was used as an antipsychotic, although it is generally not administered for this purpose now; promethazine has only approximately 1/10 of the antipsychotic strength of chlorpromazine.
- Treatment for migraines; however, other similar medications, like Compazine, have been shown to have a more favorable treatment profile, and are used almost exclusively over promethazine.
Some documented side effects include:
- Tardive dyskinesia (effects due to dopamine D2 receptor antagonism)
- Confusion in the elderly
- Drowsiness, dizziness, fatigue, more rarely vertigo
- Dry mouth
- Respiratory depression in patients under age of two and in those with severely compromised pulmonary function
- Chest discomfort/pressure (typically in cases when patient is already taking medication for high blood pressure)
- Akathisia 
- Short temper/irritability
Extremely rare side effects include:
- Neuroleptic malignant syndrome
- Euphoria (very rare, except with high IV doses and/or coadministration with opioids/CNS depressants)
Because of potential for more severe side effects, this drug is on the list to avoid in the elderly. 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.
Promethazine is listed as one of the drugs of highest anticholinergic activity in a study of anticholinergenic burden, including long-term cognitive impairment.
Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects. It acts primarily as a strong antagonist of the H1 receptor (antihistamine) and a moderate mACh receptor antagonist (anticholinergic), and also has weak to moderate affinity for the 5-HT2A, 5-HT2C, D2, and α1-adrenergic receptors, where it acts as an antagonist at all sites, as well.
Solid promethazine hydrochloride is a white to faint-yellow, practically odorless, crystalline powder. Slow oxidation may occur upon prolonged exposure to air, usually causing blue discoloration. Its hydrochloride salt is freely soluble in water and somewhat soluble in alcohol. Promethazine is a chiral compound, occurring as a mixture of enantiomers.
Promethazine was first synthesized by a group at Rhone-Poulenc (which later became part of Sanofi) led by Paul Charpentier in the early 1940s. The team was seeking to improve on diphenhydramine; the same line on medical chemistry led to the creation of chlorpromazine.
Society and culture
As of July 2017 it was 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.
It is also marketed in many combination drug formulations:
- with carbocisteine as Actithiol Antihistaminico, Mucoease, Mucoprom, Mucotal Prometazine, and Rhinathiol;
- with paracetamol as Algotropyl, Calmkid, Fevril, Phen Plus, and Velpro-P;
- with paracetamol and dextromethorphan as Choligrip na noc, Coldrex Nočná Liečba, Fedril Night Cold and Flu, Night Nurse, and Tachinotte;
- with paracetamol, phenylephrine, and salicylamide as Flukit;
- with dextromethorphan as Axcel Dextrozine and Hosedyl DM;
- with dextromethorphan and ephedrine as Methorsedyl;
- with dextromethorphan and pseudoephedrine as Sedilix-DM;
- with dextromethorphan and phenylephedrine as Sedilix-RX;
- with pholcodine as Codo-Q Junior and Tixylix;
- with pholcodine and ephedrine as Phensedyl Dry Cough Linctus;
- with pholcodine and phenylephedrine as Russedyl Compound Linctus;
- with pholcodine and phenylpropanolamine as Tripe 'P';
- with codeine as Kefei and Procodin;
- with codeine and ephedrine as Dhasedyl, Fendyl, and P.E.C. ;
- with ephedrine and dextromethorphan as Dhasedyl DM;
- with glutamic acid as Psico-Soma, and Psicosoma;
- with noscapine as Tussisedal; and
- with chlorpromazine as Vegetamin.
Product liability lawsuit
In 2009, the US Supreme Court ruled on a product liability case involving promethazine. Diana Levine, a woman suffering from a migraine, was administered Wyeth's Phenergan via IV push. The drug was injected improperly, resulting in gangrene and subsequent amputation of her right forearm below the elbow. A state jury awarded her $6 million in punitive damages.
The case was appealed to the Supreme Court on grounds of federal preemption and substantive due process. 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. In effect, this means drug manufacturers can be held liable for injuries if warnings of potential adverse effects, approved by the US Food and Drug Administration (FDA), are deemed insufficient by state courts.
On September 9, 2009, the FDA required a boxed warning be put on promethazine for injection, stating the contraindication for subcutaneous administration. The preferred administrative route is intramuscular, which reduces risk of surrounding muscle and tissue damage.
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