promethazine

Promethazine has a variety of medical uses, including:

• Sedation
• 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.{{Cite web |title=Promethazin - Anwendung, Wirkung, Nebenwirkungen {{!}} Gelbe Liste |url=https://www.gelbe-liste.de/wirkstoffe/Promethazin_22041 |access-date=22 May 2023 |website=Gelbe Liste Online |language=de | vauthors = Online GL }}
• 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.
• For moderate to severe morning sickness and hyperemesis gravidarum: In the UK, Promethazine is the drug of first choice. Promethazine is preferred during pregnancy because it is an older drug and there is more data regarding the use of it during pregnancy. Second-choice medications, which are used if Promethazine isn't tolerated or the patient cannot take it, are metoclopramide or prochlorperazine.{{cite book | author=British National Formulary | title=BNF | edition=45 |date=March 2001 | chapter=4.6 Drugs used in nausea and Vertigo - Vomiting of pregnancy}}.{{cite journal |vauthors=Southard BT, Al Khalili Y|title=Promethazine |date=2019 |journal=StatPearls|pmid=31335081}}{{CC-notice|by4}}
• For allergies such as hay fever and together with other medications in anaphylaxis
• To aid with symptoms of the common cold
• Motion sickness, including space sickness{{cite web |title=Rhea Seddon Oral History |url=https://historycollection.jsc.nasa.gov/JSCHistoryPortal/history/oral_histories/SeddonMR/SeddonMR_5-10-11.htm |website=NASA Johnson Space Center Oral History Project |access-date=25 May 2021 |date=10 May 2011}}
• Hemolytic disease of the newborn
• Anxiety before surgery
• Short-term insomnia{{cite web |title=Promethazine (Phenergan) |url=https://www.nhs.uk/medicines/Promethazine/ |website=Medicines A to Z |publisher=National Health Service |access-date=2 October 2023 |archive-url=https://web.archive.org/web/20230803160343/https://www.nhs.uk/medicines/Promethazine/ |archive-date=3 August 2023 |date=27 October 2021 |url-status=live}}

Some documented side effects include:

• Tardive dyskinesia, pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism)
• Confusion in the elderly
• Drowsiness, dizziness, fatigue, more rarely vertigo
• Known to have effects on serotonin and dopamine receptors.{{cite journal | vauthors = Schreiner NM, Windham S, Barker A | title = Atypical Neuroleptic Malignant Syndrome: Diagnosis and Proposal for an Expanded Treatment Algorithm: A Case Report | journal = A&A Case Reports | volume = 9 | issue = 12 | pages = 339–343 | date = December 2017 | pmid = 28767476 | doi = 10.1213/XAA.0000000000000610 | s2cid = 39699580 }}
• Dry mouth
• Nausea[https://bnf.nice.org.uk/drug/promethazine-hydrochloride.html National Institute for Health and Care Excellence]
• Respiratory depression in patients under the age of two and those with severely compromised pulmonary function{{Cite journal| vauthors = Hampton T |date=23 February 2005|title=Promethazine Warning|url=https://jamanetwork.com/journals/jama/article-abstract/200400|journal=JAMA|volume=293|issue=8|page=921|doi=10.1001/jama.293.8.921-c|url-access=subscription}}
• Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to its anticholinergic effects)
• Chest discomfort/pressure (In children less than 2 years old)
• Akathisia{{Cite web |url=http://www.cordingleyneurology.com/restless.html |title=Cordingley Neurology |access-date=15 February 2008 |archive-date=21 December 2016 |archive-url=https://web.archive.org/web/20161221215517/http://cordingleyneurology.com/restless.html |url-status=usurped }}

Less frequent:

• Cardiovascular side effects to include arrhythmias and hypotension
• Neuroleptic malignant syndrome
• Liver damage and cholestatic jaundice
• Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia
• Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermia

Rare side effects include:

• Seizures

Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.NCQA's HEDIS Measure: [http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf Use of High Risk Medications in the Elderly] {{webarchive|url=https://web.archive.org/web/20100201113909/http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf |date=1 February 2010 }} 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.{{cite journal |vauthors=Starke P, Weaver J, Chowdhury B | year = 2005 | title = Boxed warning added to promethazine labeling for pediatric use | journal = N. Engl. J. Med. | volume = 352 | issue = 5| page = 2653 | doi=10.1056/nejm200506233522522| pmid = 15972879 | doi-access = free }}

Promethazine is listed as one of the drugs with the highest anticholinergic activity in a study of anticholinergic burden, including long-term cognitive impairment.{{cite journal | vauthors = Salahudeen MS, Duffull SB, Nishtala PS | title = Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review | journal = BMC Geriatrics | volume = 15 | issue = 31 | pages = 31 | date = March 2015 | pmid = 25879993 | pmc = 4377853 | doi = 10.1186/s12877-015-0029-9 | doi-access = free }}

Promethazine in overdose can produce signs and symptoms including CNS depression, hypotension, respiratory depression, unconsciousness, and sudden death.{{Cite web |title=Phenergan |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf |archive-url=https://web.archive.org/web/20090818052606/http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf |url-status=dead |archive-date=18 August 2009 |access-date=30 September 2023 |website=www.accessdata.fda.gov}} Other reactions may include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes. Atypically and/or rarely, stimulation, convulsions, hyperexcitability, and nightmares may occur. Anticholinergic effects like dry mouth, dilated pupils, flushing, gastrointestinal symptoms, and delirium may occur as well. Treatment of overdose is supportive and based on symptoms.

Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects.{{cite journal |vauthors=Strenkoski-Nix LC, Ermer J, DeCleene S, Cevallos W, Mayer PR | title = Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects | journal = American Journal of Health-System Pharmacy | volume = 57 | issue = 16 | pages = 1499–505 |date=August 2000 | pmid = 10965395 | doi = 10.1093/ajhp/57.16.1499| doi-access = free }} Despite structural differences, promethazine exhibits a strikingly similar binding profile to promazine,{{Cite web |title=promazine {{!}} Ligand Activity Charts {{!}} IUPHAR/BPS Guide to PHARMACOLOGY |url=https://www.guidetopharmacology.org/GRAC/LigandActivityRangeVisForward?ligandId=7281 |access-date=18 May 2023 |website=www.guidetopharmacology.org |language=en}} another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.{{Cite book | vauthors = Möller HJ, Müller WE, Bandelow B |title=Neuroleptika – Pharmakologische Grundlagen, klinisches Wissen und therapeutisches Vorgehen |publisher=Wissenschaftliche Verlagsgesellschaft |year=2001 |isbn=978-3-8047-1773-2 |location=Stuttgart |language=German}} However, dosages used therapeutically, such as for sedation or sleep disorders, have no antipsychotic effect.{{Cite book| vauthors = Benkert O, Hippius H |date=1995 |title=Psychiatrische Pharmakotherapie |language=en |doi=10.1007/978-3-642-79084-3|isbn=978-3-540-58149-9 }} It acts primarily as a strong antagonist of the H₁ receptor (antihistamine, K_i = 1.4 nM{{cite journal | vauthors = Hill SJ, Young M | title = Antagonism of central histamine H1 receptors by antipsychotic drugs | journal = European Journal of Pharmacology | volume = 52 | issue = 3–4 | pages = 397–399 | date = December 1978 | pmid = 32056 | doi = 10.1016/0014-2999(78)90297-2 }}) and a moderate mACh receptor antagonist (anticholinergic), and also has weak to moderate affinity for the 5-HT_2A,{{cite journal |vauthors=Fiorella D, Rabin RA, Winter JC | title = The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis | journal = Psychopharmacology | volume = 121 | issue = 3 | pages = 347–56 |date=October 1995 | pmid = 8584617 | doi = 10.1007/bf02246074| s2cid = 24420080 }} 5-HT_2C, D₂,{{cite journal | vauthors = Seeman P, Watanabe M, Grigoriadis D, etal | title = Dopamine D2 receptor binding sites for agonists. A tetrahedral model | journal = Molecular Pharmacology | volume = 28 | issue = 5 | pages = 391–9 | date = November 1985 | doi = 10.1016/S0026-895X(25)14176-X | pmid = 2932631 | url = http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2932631 | access-date = 28 November 2011 | archive-date = 29 August 2021 | archive-url = https://web.archive.org/web/20210829012910/https://molpharm.aspetjournals.org/content/28/5/391.long | url-status = dead | url-access = subscription }}{{cite journal |vauthors=Burt DR, Creese I, Snyder SH | title = Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain | journal = Science | volume = 196 | issue = 4287 | pages = 326–8 |date=April 1977 | pmid = 847477 | doi = 10.1126/science.847477| bibcode = 1977Sci...196..326B }} and α₁-adrenergic receptors,{{cite book | vauthors = Prasad JP | title = Conceptual Pharmacology | url = https://books.google.com/books?id=s0e_FlM8LKYC&pg=PA295 | access-date = 27 November 2011 | year = 2010 | publisher = Universities Press | isbn = 978-81-7371-679-9 | pages = 295, 303, 598}} 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 receptor antagonist, with an EC50 of 20 μM; 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.{{cite journal | vauthors = Adolph O, Köster S, Georgieff M, Georgieff EM, Moulig W, Föhr KJ | title = Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug | journal = Neuropharmacology | volume = 63 | issue = 2 | pages = 280–291 | date = August 2012 | pmid = 22507664 | doi = 10.1016/j.neuropharm.2012.03.006 | s2cid = 35487146 }}

Another notable use of promethazine is as a local anesthetic, by blockage of sodium channels.

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.{{cite web|url=http://www.rxlist.com/cgi/generic/phenergan.htm|title=RxList: Promethazine Description|date=21 June 2007|access-date=4 June 2008|archive-url=https://web.archive.org/web/20080911231224/http://www.rxlist.com/cgi/generic/phenergan.htm|archive-date=11 September 2008|url-status=dead}}

Promethazine was first synthesized by a group at Rhone-Poulenc (which later became part of Sanofi) led by Paul Charpentier in the 1940s.{{cite journal | vauthors = Ban TA | title = The role of serendipity in drug discovery | journal = Dialogues in Clinical Neuroscience | volume = 8 | issue = 3 | pages = 335–44 | date = 2006 | pmid = 17117615 | pmc = 3181823 | doi = 10.31887/DCNS.2006.8.3/tban }} The team was seeking to improve on diphenhydramine; the same line of medical chemistry led to the creation of chlorpromazine.{{cite web|title=Paul Charpentier, Henri-Marie Laborit, Simone Courvoisier, Jean Delay, and Pierre Deniker|url=https://www.sciencehistory.org/historical-profile/paul-charpentier-henri-marie-laborit-simone-courvoisier-jean-delay-and-pierre|publisher=Science History Institute|access-date=20 March 2018|language=en|date=6 August 2015|archive-date=20 March 2018|archive-url=https://web.archive.org/web/20180320230738/https://www.sciencehistory.org/historical-profile/paul-charpentier-henri-marie-laborit-simone-courvoisier-jean-delay-and-pierre|url-status=dead}}

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.

File:Atosil.jpg

It is also marketed in many combination drug formulations:

• with carbocisteine as Actithiol Antihistaminico, Mucoease, Mucoprom, Mucotal Prometazine, and Rhinathiol;
• with paracetamol (acetaminophen) 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 Triple '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 and phenobarbital as Vegetamin.

The recreational drug lean, also known as purple drank among other names, often contains a combination of promethazine with codeine-containing cold medication.{{cite journal | vauthors = Agnich LE, Stogner JM, Miller BL, Marcum CD | title = Purple drank prevalence and characteristics of misusers of codeine cough syrup mixtures | journal = Addictive Behaviors | volume = 38 | issue = 9 | pages = 2445–9 | date = September 2013 | pmid = 23688907 | doi = 10.1016/j.addbeh.2013.03.020 | url = http://libres.uncg.edu/ir/asu/f/Marcum_Catherine_2013_Purple_drank_orig.X.pdf }}

{{Main|Wyeth v. Levine}}

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.{{cite news | vauthors = Liptak A |url=https://www.nytimes.com/2008/09/19/us/19scotus.html |title=Drug Label, Maimed Patient and Crucial Test for Justices |work=The New York Times |date=18 September 2001 |access-date=31 October 2008}} 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.{{cite news | vauthors = Stout D |url=https://www.nytimes.com/2009/03/05/washington/05scotus.html |title=Drug Approval Is Not a Shield From Lawsuits, Justices Rule |work=The New York Times |date=4 March 2009 |access-date=4 March 2009}} 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.

In September 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 the risk of surrounding muscle and tissue damage.{{cite web|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm182169.htm|archive-url=https://web.archive.org/web/20090921025943/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm182169.htm|url-status=dead|archive-date=21 September 2009|title=Information for Healthcare Professionals: Intravenous Promethazine and Severe Tissue Injury, Including Gangrene|website=Food and Drug Administration|date=15 August 2013}}

{{Reflist}}

{{Navboxes

| title = Medical uses

| titlestyle = background:#ccccff

| list1 =

{{Antiemetics}}

{{Antipruritics}}

{{Hypnotics}}

{{Antihistamines}}

}}

{{Navboxes

| title = Pharmacodynamics

| titlestyle = background:#ccccff

| list1 =

{{Adrenergic receptor modulators}}

{{Dopamine receptor modulators}}

{{Histamine receptor modulators}}

{{Ion channel modulators}}

{{Muscarinic acetylcholine receptor modulators}}

{{Serotonin receptor modulators}}

{{Sigma receptor modulators}}

}}

{{Tricyclics}}

{{Subject bar|auto=y|d=y}}

{{Portal bar|Medicine}}

{{Authority control}}

Category:Antiemetics

Category:Antimigraine drugs

Category:CYP2D6 inhibitors

Category:Dimethylamino compounds

Category:H1 receptor antagonists

Category:HERG blocker

Category:Hypnotics

Category:M1 receptor antagonists

Category:M2 receptor antagonists

Category:M3 receptor antagonists

Category:M4 receptor antagonists

Category:M5 receptor antagonists

Category:NMDA receptor antagonists

Category:Phenothiazines

Category:Sodium channel blockers

Category:Sigma receptor modulators

Category:Wikipedia medicine articles ready to translate