Promethazine
Promethazine is a first-generation antihistamine and antiemetic used to treat allergies, insomnia, and nausea. It was once widely used as an antipsychotic, although it is generally not used for this purpose now. It has approximately 1/10 the antipsychotic strength of chlorpromazine. It may also help with some symptoms associated with the common cold and may also be used for sedating people who are agitated or anxious. Promethazine is available by mouth in syrup or tablet dosage forms, as a rectal suppository, or by injection into a muscle. Common side effects of promethazine include confusion and sleepiness; consumption of  alcohol or other sedatives can make these symptoms worse. It is unclear if use of promethazine during pregnancy or breastfeeding is safe for the baby. Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing. Use of promethazine by injection into a vein is not recommended, due to potential skin damage. Promethazine is in the phenothiazine family of medications. Promethazine was made in the 1940s by a team of scientists from Rhône-Poulenc laboratories. It was approved for medical use in the United States in 1951. It is a generic  medication and is available under many brand names globally. In 2019, it was the 174th most commonly prescribed medication in the United States, with more than 3million prescriptions. Medical uses. Promethazine has a variety of medical uses, including: Side effects. Some documented side effects include: Less frequent: Rare side effects include: 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. Pharmacology. 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 H receptor (antihistamine) and a moderate mACh receptor antagonist (anticholinergic), and also has weak to moderate affinity for the 5-HT, 5-HT, D,and α-adrenergic receptors, where it acts as an antagonist at all sites, as well. New studies have shown  that promethazine acts as a strong non-competetive selective NMDA receptor antagonist; which might promote sedation in addition with the strong antihistaminergic effects of the H receptor, but also as a weaker analgesic. It does not however affect the AMPA receptors. Another notable use of promethazine is as a local anesthetic, by blockade of sodium channels. Chemistry. 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. 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. 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: Recreational use. The recreational drug lean, also known as purple drank among other names, often contains a combination of promethazine with codeine-containing cold medication. 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.