Common side effects of promethazine include confusion and sleepiness;[6] consumption ofalcohol or other sedatives can make these symptoms worse.[6] It is unclear if use of promethazine duringpregnancy orbreastfeeding is safe for the fetus.[6][8] Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing.[6] Use of promethazine by injection into a vein is not recommended, due to potential skin damage.[6] Promethazine is in thephenothiazine family of medications.[6] It is also a stronganticholinergic, which produces itssedative effects. This also means high or toxic doses can act as adeliriant.[10]
Promethazine was made in the 1940s by a team of scientists fromRhône-Poulenc laboratories.[11] It was approved for medical use in the United States in 1951.[6] 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 1million prescriptions;[12][13] and the combination withdextromethorphan was the 252nd most commonly prescribed medication in the United States, with more than 1million prescriptions.[14][15]
In Germany, it is approved for the treatment of agitation and agitation associated with underlying psychiatric disorders with a maximum daily dose of 200 mg.[17]
For nausea and vomiting associated with anesthesia or chemotherapy. It is commonly used postoperatively as anantiemetic. The antiemetic activity increases with increased dosing; however, side effects also increase, which often limits maximal dosing.[16]
For moderate to severemorning sickness andhyperemesis gravidarum: In theUK, Promethazine is thedrug of first choice. Promethazine is preferred during pregnancy because it is an older drug and there is more data regarding the use of it duringpregnancy. Second-choice medications, which are used if Promethazine isn't tolerated or the patient cannot take it, aremetoclopramide orprochlorperazine.[18][16]
Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.[24] 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.[25]
Promethazine is listed as one of the drugs with the highest anticholinergic activity in a study of anticholinergic burden, including long-term cognitive impairment.[26]
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,[28] another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.[29] However, dosages used therapeutically, such as for sedation, have no antipsychotic effect.[30] It acts primarily as a strongantagonist of theH1 receptor (antihistamine,Ki = 1.4 nM[31]) and a moderatemACh receptor antagonist (anticholinergic),[4] and also has weak to moderateaffinity for the5-HT2A,[32]5-HT2C,[32]D2,[33][34] andα1-adrenergic receptors,[35] 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;[36] 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.[36]
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.[44]
Promethazine was first synthesized by a group atRhone-Poulenc (which later became part ofSanofi) led by Paul Charpentier in the 1940s.[45] The team was seeking to improve ondiphenhydramine; the same line of medical chemistry led to the creation ofchlorpromazine.[46]
The recreational druglean, also known as purple drank among other names, often contains a combination of promethazine with codeine-containingcold medication.[7]
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.[47] 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.[48] 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.[49]
^abcdefghijklmnSouthard BT, Al Khalili Y (2019). "Promethazine".StatPearls.PMID31335081. This article incorporates text available under theCC BY 4.0 license.
^British National Formulary (March 2001). "4.6 Drugs used in nausea and Vertigo - Vomiting of pregnancy".BNF (45 ed.)..
^"Rhea Seddon Oral History".NASA Johnson Space Center Oral History Project. 10 May 2011. Retrieved25 May 2021.
^Schreiner NM, Windham S, Barker A (December 2017). "Atypical Neuroleptic Malignant Syndrome: Diagnosis and Proposal for an Expanded Treatment Algorithm: A Case Report".A&A Case Reports.9 (12):339–343.doi:10.1213/XAA.0000000000000610.PMID28767476.S2CID39699580.
^Hill SJ, Young M (December 1978). "Antagonism of central histamine H1 receptors by antipsychotic drugs".European Journal of Pharmacology.52 (3–4):397–399.doi:10.1016/0014-2999(78)90297-2.PMID32056.
^abFiorella D, Rabin RA, Winter JC (October 1995). "The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis".Psychopharmacology.121 (3):347–56.doi:10.1007/bf02246074.PMID8584617.S2CID24420080.
^abBruno C, Cavalluzzi MM, Rusciano MR, Lovece A, Carrieri A, Pracella R, et al. (June 2016). "The chemosensitizing agent lubeluzole binds calmodulin and inhibits Ca(2+)/calmodulin-dependent kinase II".European Journal of Medicinal Chemistry.116:36–45.doi:10.1016/j.ejmech.2016.03.045.PMID27043269.
^abNakai T, Kitamura N, Hashimoto T, Kajimoto Y, Nishino N, Mita T, et al. (August 1991). "Decreased histamine H1 receptors in the frontal cortex of brains from patients with chronic schizophrenia".Biological Psychiatry.30 (4):349–356.doi:10.1016/0006-3223(91)90290-3.PMID1912125.S2CID9715772.
^Vogtherr M, Grimme S, Elshorst B, Jacobs DM, Fiebig K, Griesinger C, et al. (August 2003). "Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein".Journal of Medicinal Chemistry.46 (17):3563–3564.doi:10.1021/jm034093h.PMID12904059.
^Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, et al. (October 2008). "Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1".Journal of Medicinal Chemistry.51 (19):5932–5942.doi:10.1021/jm8003152.PMID18788725.
This article incorporates text available under theCC BY 4.0 license.
