Chemistry:Promethazine

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Short description: Pharmaceutical drug
Promethazine
Promethazine.svg
Promethazine-based-on-xtal-3D-bs-17.png
Clinical data
Trade namesPhenergan, many others[1]
AHFS/Drugs.comMonograph
MedlinePlusa682284
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, rectal, intravenous, intramuscular, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability[2]
Protein binding93%
MetabolismLiver glucuronidation and sulfoxidation
Elimination half-life10–19 hours[2][3]
ExcretionKidney and biliary
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H20N2S
Molar mass284.42 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine, antipsychotic, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold[4] and may also be used for sedating people who are agitated or anxious, an effect that has led to some recreational use (especially with codeine).[5][6][7] Promethazine is taken by mouth (oral), as a rectal suppository, or by injection into a muscle (IM).[4]

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 fetus.[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 2 million prescriptions.[9][10]

Medical uses

Promethazine has a variety of medical uses, including:

Side effects

Some documented side effects include:

  • Tardive dyskinesia, pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism)[11]
  • Confusion in the elderly[11]
  • Drowsiness, dizziness, fatigue, more rarely vertigo
  • Known to have effects on serotonin and dopamine receptors.[16]
  • Dry mouth[11]
  • Nausea[17]
  • Respiratory depression in patients under age of two and in those with severely compromised pulmonary function[18]
  • Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to its anti-cholinergic effects)[11]
  • Chest discomfort/pressure (In children less than 2 years old)[11]
  • Akathisia[19]

Less frequent:

  • Cardiovascular side effects to include arrhythmias and hypotension[11]
  • Neuroleptic malignant syndrome[11]
  • Liver damage and cholestatic jaundice[11]
  • Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia[11]
  • Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermia[11]

Rare side effects include:

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly.[20] 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.[21]

Promethazine is listed as one of the drugs of highest anticholinergic activity in a study of anticholinergenic burden, including long-term cognitive impairment.[22]

Overdose

Promethazine in overdose can produce signs and symptoms including CNS depression, hypotension, respiratory depression, unconsciousness, and sudden death.[23] Other reactions may include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-planar reflexes.[23] Atypically and/or rarely, stimulation, convulsions, hyperexcitability, and nightmares may occur.[23] Anticholinergic effects like dry mouth, dilated pupils, flushing, gastrointestinal symptoms, and delirium may occur as well.[23] Treatment of overdose is supportive and based on symptoms.[23]

Pharmacology

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,[24] another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.[25] However, dosages used therapeutically, such as for sedation or sleep disorders, have no antipsychotic effect.[26] It acts primarily as a strong antagonist of the H1 receptor (antihistamine, Ki = 1.4 nM[27]) and a moderate mACh receptor antagonist (anticholinergic),[2] and also has weak to moderate affinity for the 5-HT2A,[28] 5-HT2C,[28] D2,[29][30] and α1-adrenergic receptors,[31] 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;[32] 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.[32]

Another notable use of promethazine is as a local anesthetic, by blockage of sodium channels.[31]

Binding to receptors in nM (Ki)
receptor Ki (nM) ref
α1A-adrenoceptor (Rat) 32 [33]
α1B-adrenoceptor (Rat) 21 [33]
α1D-adrenoceptor (Human) 90 [33]
α2A-adrenoceptor (Human) 256 [33]
α2B-adrenoceptor (Human) 24 [33]
α2C-adrenoceptor (Human) 353 [33]
Calmodulin (Human) 60000 [34][33][35]
Calmodulin (Bovine) 50000 [34][35][33]
Chloroquine resistance transporter (Plasmodium falciparum) 85000 [36][33]
D1 receptor (Human) 1372 [33]
D2 receptor (Human) 260 [33]
D3 receptor (Human) 190 [33]
H1 receptor (Human) 0.33[33]-1.4[37] [37][33]
H2 receptor (Human) 1146 [33]
M1 receptor (Human) 3.32 [33]
M2 receptor (Human) 12 [33]
M3 receptor (Human) 4.15 [33]
M4 receptor (Human) 1.06 [33]
M5 receptor (Human) 3.31 [33]
NET (Human) 4203 [33]
Prion protein (Human) 8000 [38][33]
5-HT1A receptor (Rat) 1484 [33]
5-HT2A receptor (Human) 19 [33]
5-HT2B receptor (Human) 43 [33]
5-HT2C receptor (Human) 6.48 [33]
5-HT6 receptor (Human) 1128 [33]
SERT (Serotonin transporter) (Human) 2130 [33]
Sigma1 receptor (Human) 120 [33]
OCT1 (Human) 35100 [39][33]

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.[40]

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.[41] The team was seeking to improve on diphenhydramine; the same line on medical chemistry led to the creation of chlorpromazine.[42]

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]

Atosil syrup

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.[5]

Product liability lawsuit

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.[43] 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.[44] 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.[45]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Promethazine international brands". Drugs.com. https://www.drugs.com/international/promethazine.html. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects". American Journal of Health-System Pharmacy 57 (16): 1499–505. August 2000. doi:10.1093/ajhp/57.16.1499. PMID 10965395. 
  3. ↑ "Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines)". Clinical Pharmacokinetics 10 (6): 477–97. 1985. doi:10.2165/00003088-198510060-00002. PMID 2866055. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 "Promethazine Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/promethazine-hydrochloride.html. 
  5. ↑ 5.0 5.1 "Purple drank prevalence and characteristics of misusers of codeine cough syrup mixtures". Addictive Behaviors 38 (9): 2445–9. September 2013. doi:10.1016/j.addbeh.2013.03.020. PMID 23688907. http://libres.uncg.edu/ir/asu/f/Marcum_Catherine_2013_Purple_drank_orig.X.pdf. 
  6. ↑ 6.0 6.1 British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. p. 276. ISBN 978-0857112989. 
  7. ↑ (in en) Sedation: A Guide to Patient Management. Elsevier Health Sciences. 2009. p. 113. ISBN 978-0323075961. https://books.google.com/books?id=Abp9ci5-n1wC&pg=PA113. 
  8. ↑ Laughing Gas, Viagra, and Lipitor: The Human Stories behind the Drugs We Use. United Kingdom: Oxford University Press. 2006. p. 146. ISBN 9780199885282. https://books.google.com/books?id=Z-4AQEqbE-MC&pg=PT146. Retrieved July 9, 2016. 
  9. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Promethazine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Promethazine. 
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 "Promethazine". StatPearls. 2019. PMID 31335081.  This article incorporates text available under the CC BY 4.0 license.
  12. ↑ Online, Gelbe Liste. "Promethazin - Anwendung, Wirkung, Nebenwirkungen | Gelbe Liste" (in de). https://www.gelbe-liste.de/wirkstoffe/Promethazin_22041. 
  13. ↑ British National Formulary (March 2001). "4.6 Drugs used in nausea and Vertigo - Vomiting of pregnancy". BNF (45 ed.). .
  14. ↑ "Rhea Seddon Oral History". 10 May 2011. https://historycollection.jsc.nasa.gov/JSCHistoryPortal/history/oral_histories/SeddonMR/SeddonMR_5-10-11.htm. 
  15. ↑ "Promethazine (Phenergan)". National Health Service. 27 October 2021. https://www.nhs.uk/medicines/Promethazine/. 
  16. ↑ "Atypical Neuroleptic Malignant Syndrome: Diagnosis and Proposal for an Expanded Treatment Algorithm: A Case Report". A&A Case Reports 9 (12): 339–343. December 2017. doi:10.1213/XAA.0000000000000610. PMID 28767476. 
  17. ↑ National Institute for Health and Care Excellence
  18. ↑ "Promethazine Warning". JAMA 293 (8): 921. 23 February 2005. doi:10.1001/jama.293.8.921-c. https://jamanetwork.com/journals/jama/article-abstract/200400. 
  19. ↑ "Cordingley Neurology". http://www.cordingleyneurology.com/restless.html. 
  20. ↑ NCQA's HEDIS Measure: Use of High Risk Medications in the Elderly
  21. ↑ "Boxed warning added to promethazine labeling for pediatric use". N. Engl. J. Med. 352 (5): 2653. 2005. doi:10.1056/nejm200506233522522. PMID 15972879. 
  22. ↑ "Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review". BMC Geriatrics 15 (31): 31. March 2015. doi:10.1186/s12877-015-0029-9. PMID 25879993. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 "Phenergan". https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf. 
  24. ↑ "promazine | Ligand Activity Charts | IUPHAR/BPS Guide to PHARMACOLOGY" (in en). https://www.guidetopharmacology.org/GRAC/LigandActivityRangeVisForward?ligandId=7281. 
  25. ↑ (in German) Neuroleptika – Pharmakologische Grundlagen, klinisches Wissen und therapeutisches Vorgehen. Stuttgart: Wissenschaftliche Verlagsgesellschaft. 2001. ISBN 978-3804717732. 
  26. ↑ (in en) Psychiatrische Pharmakotherapie. 1995. doi:10.1007/978-3-642-79084-3. ISBN 978-3-540-58149-9. 
  27. ↑ "Antagonism of central histamine H1 receptors by antipsychotic drugs". European Journal of Pharmacology 52 (3–4): 397–399. December 1978. doi:10.1016/0014-2999(78)90297-2. PMID 32056. 
  28. ↑ 28.0 28.1 "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. October 1995. doi:10.1007/bf02246074. PMID 8584617. 
  29. ↑ "Dopamine D2 receptor binding sites for agonists. A tetrahedral model". Molecular Pharmacology 28 (5): 391–9. November 1985. PMID 2932631. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2932631. Retrieved 2011-11-28. 
  30. ↑ "Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain". Science 196 (4287): 326–8. April 1977. doi:10.1126/science.847477. PMID 847477. Bibcode: 1977Sci...196..326B. 
  31. ↑ 31.0 31.1 Jagadish Prasad, P. (2010). Conceptual Pharmacology. Universities Press. pp. 295, 303, 598. ISBN 978-81-7371-679-9. https://books.google.com/books?id=s0e_FlM8LKYC&pg=PA295. Retrieved 27 November 2011. 
  32. ↑ 32.0 32.1 "Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug". Neuropharmacology 63 (2): 280–291. August 2012. doi:10.1016/j.neuropharm.2012.03.006. PMID 22507664. 
  33. ↑ 33.00 33.01 33.02 33.03 33.04 33.05 33.06 33.07 33.08 33.09 33.10 33.11 33.12 33.13 33.14 33.15 33.16 33.17 33.18 33.19 33.20 33.21 33.22 33.23 33.24 33.25 33.26 33.27 33.28 33.29 "promethazine | Ligand Activity Charts | IUPHAR/BPS Guide to PHARMACOLOGY" (in en). https://www.guidetopharmacology.org/GRAC/LigandActivityRangeVisForward?ligandId=7282. 
  34. ↑ 34.0 34.1 "The chemosensitizing agent lubeluzole binds calmodulin and inhibits Ca(2+)/calmodulin-dependent kinase II". European Journal of Medicinal Chemistry 116: 36–45. June 2016. doi:10.1016/j.ejmech.2016.03.045. PMID 27043269. 
  35. ↑ 35.0 35.1 "Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction". ACS Medicinal Chemistry Letters 4 (3): 353–357. March 2013. doi:10.1021/ml300467n. PMID 24900672. 
  36. ↑ "Chlorpheniramine Analogues Reverse Chloroquine Resistance in Plasmodium falciparum by Inhibiting PfCRT". ACS Medicinal Chemistry Letters 5 (5): 576–581. May 2014. doi:10.1021/ml5000228. PMID 24900883. 
  37. ↑ 37.0 37.1 "Decreased histamine H1 receptors in the frontal cortex of brains from patients with chronic schizophrenia". Biological Psychiatry 30 (4): 349–356. August 1991. doi:10.1016/0006-3223(91)90290-3. PMID 1912125. 
  38. ↑ "Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein". Journal of Medicinal Chemistry 46 (17): 3563–3564. August 2003. doi:10.1021/jm034093h. PMID 12904059. 
  39. ↑ "Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1". Journal of Medicinal Chemistry 51 (19): 5932–5942. October 2008. doi:10.1021/jm8003152. PMID 18788725. 
  40. ↑ "RxList: Promethazine Description". 2007-06-21. http://www.rxlist.com/cgi/generic/phenergan.htm. 
  41. ↑ "The role of serendipity in drug discovery". Dialogues in Clinical Neuroscience 8 (3): 335–44. 2006. doi:10.31887/DCNS.2006.8.3/tban. PMID 17117615. 
  42. ↑ "Paul Charpentier, Henri-Marie Laborit, Simone Courvoisier, Jean Delay, and Pierre Deniker" (in en). Science History Institute. August 6, 2015. https://www.sciencehistory.org/historical-profile/paul-charpentier-henri-marie-laborit-simone-courvoisier-jean-delay-and-pierre. 
  43. ↑ "Drug Label, Maimed Patient and Crucial Test for Justices". The New York Times. 2001-09-18. https://www.nytimes.com/2008/09/19/us/19scotus.html. 
  44. ↑ "Drug Approval Is Not a Shield From Lawsuits, Justices Rule". The New York Times. 2009-03-04. https://www.nytimes.com/2009/03/05/washington/05scotus.html. 
  45. ↑ "Information for Healthcare Professionals: Intravenous Promethazine and Severe Tissue Injury, Including Gangrene". 2013-08-15. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm182169.htm. 

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