Promethazine

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Promethazine
Promethazine.svg
1:1 mixture (racemate)
Systematic (IUPAC) name
(RS)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine
Clinical data
Trade names Phenergan
AHFS/Drugs.com monograph
MedlinePlus a682284
Pregnancy cat.
Legal status
Routes Oral, rectal, IV, IM, topical
Pharmacokinetic data
Bioavailability 88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability[1]
Protein binding 93%
Metabolism Hepatic glucuronidation and sulfoxidation
Half-life 16-19 hours[1][2]
Excretion Renal and biliary
Identifiers
CAS number 60-87-7 YesY
58-33-3 (hydrochloride)
ATC code D04AA10 R06AD02
PubChem CID 4927
DrugBank DB01069
ChemSpider 4758 YesY
UNII FF28EJQ494 YesY
KEGG D00494 YesY
ChEBI CHEBI:8461 YesY
ChEMBL CHEMBL643 YesY
Chemical data
Formula C17H20N2S 
Mol. mass 284.42 g/mol
 YesY (what is this?)  (verify)

Promethazine is a neuroleptic medication and first-generation antihistamine of the phenothiazine family. The drug has strong sedative and weak antipsychotic effects. It also reduces motion sickness and has antiemetic and anticholinergic properties. In some countries it is prescribed for insomnia when benzodiazepines are contraindicated. It is available in many countries under the brand names Phenergan, Promethegan, Romergan, Fargan, Farganesse, Prothiazine, Avomine, Atosil, Receptozine, Lergigan, and (in the UK) Sominex.[3]

Indications[edit]

Chemistry[edit]

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 (pictured).[7]

Promethazine, 10-(2-dimethylaminopropyl)phenothiazine, is synthesized by alkylating phenothiazine with 1-chloro-2-(dimethylamino)propane in the presence of sodium amide:[8][9][10]

Promethazine synthesis.svg

Pharmacology[edit]

Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects.[1] It acts primarily as a strong antagonist of the H1 receptor (antihistamine) and a moderate mACh receptor antagonist (anticholinergic),[1] and also has weak to moderate affinity for the 5-HT2A,[11] 5-HT2C,[11] D2,[12][13] and α1-adrenergic receptors,[14] where it acts as an antagonist at all sites, as well.

Another notable use of promethazine is as a local anesthetic, by blockade of sodium channels.[14]

Side effects[edit]

Some common side effects include:

  • Tardive dyskinesia
  • Confusion in the elderly
  • Drowsiness, dizziness, fatigue, more rarely vertigo
  • Dry mouth
  • Respiratory depression in patients under age of two and in those with severely compromised pulmonary function
  • Constipation
  • Chest discomfort/pressure (typically in cases when patient is already taking medication for high blood pressure)
  • Euphoria (very rare, except with high IV doses and/or coadministration with opioids/CNS depressants)
  • Akathisia [15]
  • Paresthesia
  • Short temper/irritability

Extremely rare side effects include:

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly. (See NCQA’s HEDIS Measure: Use of High Risk Medications 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 apnoea. [16]

Product liability lawsuit[edit]

Main article: Wyeth v. Levine

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.[17] 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.[18] 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 black box warning for injection be put on promethazine, stating the contraindication for subcutaneous administration. The preferred administrative route is intramuscular, which reduces risk of surrounding muscle and tissue damage.[19]

See also[edit]

  • Purple drank (a recreational drug concoction containing promethazine)

References[edit]

  1. ^ a b c d Strenkoski-Nix LC, Ermer J, DeCleene S, Cevallos W, Mayer PR (August 2000). "Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects". American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists 57 (16): 1499–505. PMID 10965395. 
  2. ^ Paton DM, Webster DR (1985). "Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines)". Clinical Pharmacokinetics 10 (6): 477–97. doi:10.2165/00003088-198510060-00002. PMID 2866055. 
  3. ^ RxList: Promethazine
  4. ^ a b c d e RxList Indications for Promethazine
  5. ^ British National Formulary (March 2001). "4.6 Drugs used in nausea and Vertigo - Vomiting of pregnancy". BNF (45 ed.). .
  6. ^ http://www.cja-jca.org/cgi/reprint/6/4/375.pdf[dead link]
  7. ^ "RxList: Promethazine Description". 2007-06-21. 
  8. ^ Beringer, Paul; Troy, David A.; Remington, Joseph P. (2006). Remington: The Science and Practice of Pharmacy. Hagerstown, MD: Lippincott Williams & Wilkins. p. 1545. ISBN 0-7817-4673-6. 
  9. ^ P. Charpentier, U.S. Patent 2,530,451 (1950)
  10. ^ S.B. Sidney, J.A. Nicholson, U.S. Patent 2,607,773 (1952)
  11. ^ a b Fiorella 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. PMID 8584617. 
  12. ^ Seeman P, Watanabe M, Grigoriadis D, et al. (November 1985). "Dopamine D2 receptor binding sites for agonists. A tetrahedral model". Molecular Pharmacology 28 (5): 391–9. PMID 2932631. 
  13. ^ Burt DR, Creese I, Snyder SH (April 1977). "Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain". Science 196 (4287): 326–8. doi:10.1126/science.847477. PMID 847477. 
  14. ^ a b Jagadish Prasad, P. (2010). Conceptual Pharmacology. Universities Press. pp. 295, 303, 598. ISBN 978-81-7371-679-9. Retrieved 27 November 2011. 
  15. ^ Cordingley Neurology
  16. ^ Starke P, Weaver J, Chowdhury B (2005). "Boxed warning added to promethazine labeling for pediatric use". N Eng J Med. 352 (5): 2653. doi:10.1056/nejm200506233522522. 
  17. ^ Liptak, Adam (2001-09-18). "Drug Label, Maimed Patient and Crucial Test for Justices". The New York Times. Retrieved 2008-10-31. 
  18. ^ Stout, David (2009-03-04). "Drug Approval Is Not a Shield From Lawsuits, Justices Rule". The New York Times. Retrieved 2009-03-04. 
  19. ^ "Information for Healthcare Professionals: Intravenous Promethazine and Severe Tissue Injury, Including Gangrene". 2013-08-15. 

External links[edit]

  • "Promethazine". U.S. National Library of Medicine and National Institutes of Health.