Common side effects of promethazine include confusion and sleepiness;[4] consumption of alcohol or other sedatives can make these symptoms worse.[4] It is unclear if use of promethazine during pregnancy or breastfeeding is safe for the baby.[4][6] Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing.[4] Use of promethazine by injection into a vein is not recommended, due to potential skin damage.[4] Promethazine is in the phenothiazine family of medications.[4] It is also a moderate anticholinergic, which produces its sedative effects. This also means high doses act as a deliriant.[2]
Promethazine was made in the 1940s by a team of scientists from Rhône-Poulenc laboratories.[8] It was approved for medical use in the United States in 1951.[4] It is a generic medication and is available under many brand names globally.[1] In 2020, it was the 208th most commonly prescribed medication in the United States, with more than 2million prescriptions.[9][10]
Medical uses
Promethazine has a variety of medical uses, including:
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.[12]
For nausea and vomiting associated with anesthesia or chemotherapy. It is commonly used postoperatively as an antiemetic. The antiemetic activity increases with increased dosing; however, side effects also increase, which often limits maximal dosing.[11]
Because of potential for more severe side effects, this drug is on the list to avoid in the elderly.[19] 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.[20]
Promethazine is listed as one of the drugs of highest anticholinergic activity in a study of anticholinergenic burden, including long-term cognitive impairment.[21]
Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects.[2] Despite structural differences, promethazine exhibits a strikingly similar binding profile to promazine,[23] another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.[24] However, dosages used therapeutically, such as for sedation or sleep disorders, have no antipsychotic effect.[25] It acts primarily as a strong antagonist of the H1 receptor (antihistamine, Ki = 1.4 nM[26]) and a moderate mACh receptor antagonist (anticholinergic),[2] and also has weak to moderate affinity for the 5-HT2A,[27]5-HT2C,[27]D2,[28][29] and α1-adrenergic receptors,[30] where it acts as an antagonist at all sites, as well. New studies have shown that promethazine acts as a strong non-competitive selective NMDA receptorantagonist, with an EC50 of 20 μM;[31] which might promote sedation in addition with the strong antihistaminergic effects of the H1 receptor, but also as a weaker analgesic. It does not however affect the AMPA receptors.[31]
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 hydrochloridesalt is freely soluble in water and somewhat soluble in alcohol. Promethazine is a chiral compound, occurring as a mixture of enantiomers.[39]
History
Promethazine was first synthesized by a group at Rhone-Poulenc (which later became part of Sanofi) led by Paul Charpentier in the early 1940s.[40] The team was seeking to improve on diphenhydramine; the same line on medical chemistry led to the creation of chlorpromazine.[41]
Society and culture
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]
The recreational drug lean, also known as purple drank among other names, often contains a combination of promethazine with codeine-containing cold medication.[5]
In 2009, the US Supreme Court ruled on a product liability case involving promethazine. Diana Levine, a woman with 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.[42] 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.[43] 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.[44]
^ abcdefghijklmnSouthard BT, Al Khalili Y (2019). "Promethazine". StatPearls. PMID31335081. This article incorporates text available under the CC 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. Retrieved 25 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, Tanaka C (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, Zahn R (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.
