Orphenadrine

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Orphenadrine
(RS)-Orphenadrin Structural Formula V1.svg
Clinical data
Trade names Generic; many brand names worldwide[1]
AHFS/Drugs.com Monograph
MedlinePlus a682162
Pregnancy
category
  • AU: B2
  • US: C (Risk not ruled out)
Routes of
administration
Oral, intravenous, intramuscular
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 90%
Protein binding 95%
Metabolism Hepatic demethylation
Elimination half-life 13-20 hours[2]
Excretion Renal and biliary
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.001.372 Edit this at Wikidata
Chemical and physical data
Formula C18H23NO
Molar mass 269.381 g/mol
3D model (JSmol)
  (verify)

Orphenadrine (sold under many brand names worldwide[1]) is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to diphenhydramine. It is used to treat muscle pain and to help with motor control in Parkinson's disease, but has largely been superseded by newer drugs. It was discovered and developed in the 1940s.

As of 2015 the cost for a typical month of medication in the United States is US$25 to 50.[3]

Medical use[edit]

Orphenadrine is used to relieve pain caused by muscle injuries like strains and sprains in combination with rest and physical therapy.[4] A 2004 review found fair evidence that orphenadrine is effective for acute back or neck pain, but found insufficient evidence to establish the relative efficacy of the drug in relation to other drugs in the study.[5]

Orphenadrine and other muscle relaxants are sometimes used to treat pain arising from rheumatoid arthritis but there is no evidence they are effective for that purpose.[6]

A 2003 Cochrane Review of the use of anticholinergic drugs to improve motor function in Parkinson's disease found that as a class, the drugs are useful for that purpose; it identified one single-site randomised, cross-over study of orphenadrine vs placebo.[7] Orphenadrine and other anticholinergics have largely been superseded by other drugs; they have a use in alleviating motor function symptoms, and appear to help about 20% of people with Parkinson's.[8]

Side effects[edit]

Orphenadrine has the side effects of the other common antihistamines in large part. Stimulation is somewhat more common than with other related antihistamines, and is especially common in the elderly. Common side effects include dry mouth, dizziness, drowsiness, upset stomach or vomiting, constipation, urine retention, blurred vision, and headache.[4] Its use in Parkinson's is especially limited by these factors.[7]

People with glaucoma, digestive problems such as peptic ulcers or bowel obstruction, or sphincter relaxation disorders, or with enlarged prostate, bladder problems, or myasthenia gravis, should not take this drug.[9]

Pharmacology[edit]

Orphenadrine is known to have this pharmacology:

Chemistry[edit]

Orphenadrine is a derivative of diphenhydramine with a methyl group added to one of the phenyl rings.[18]

Tofenacin is the N-desmethyl analogue of orphenadrine and an antidepressant.

Nefopam is a cyclized analogue of orphenadrine and diphenhydramine, with each different from one another only by the presence of one or two carbons.[19][20][21] It is used as an analgesic.

Preparations[edit]

Orphenadrine has been available as a citrate salt and a hydrochloride salt; in the US as of February 2016 the citrate form was available in tablets, extended release tablets, and by injection for acute use in a hospital setting.[1][22]

Orphenadrine is often available mixed with aspirin, paracetamol/acetaminophen, ibuprofen, caffeine, and/or codeine.[1]

Stereochemistry[edit]

Orphenadrine contains a stereocenter and consists of two enantiomers. This is a racemate, ie a 1: 1 mixture of the ( R ) - and the ( S ) - form:[23]

Enantiomers of orphenadrine
(R)-Orphenadrin Structural Formula V1.svg
CAS-Nummer: 33425-91-1
(S)-Orphenadrin Structural Formula V1.svg
CAS-Nummer: 33425-89-7

History[edit]

George Rieveschl was a professor of chemistry at the University of Cincinnati and led a research program working on antihistamines. In 1943, one of his students, Fred Huber, synthesized diphenhydramine. Rieveschl worked with Parke-Davis to test the compound, and the company licensed the patent from him. In 1947 Parke-Davis hired him as their Director of Research. While he was there, he led the development of orphenadrine, an analog of diphenhydramine.[24]

Prior to the development of amantadine in the late 1960s and then other drugs, anticholinergics like orphenadrine were the mainstay of Parkinson's treatment.[8]

References[edit]

  1. ^ a b c d Drugs.com international listings for orphenadrine Page accessed Feb 5, 2016
  2. ^ Labout, JJ; Thijssen, C; Keijser, GG; Hespe, W (1982). "Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man". European journal of clinical pharmacology. 21 (4): 343–50. doi:10.1007/BF00637624. PMID 7056281. 
  3. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 2. ISBN 9781284057560. 
  4. ^ a b Medline Plus. Medline Plus entry for Orphenadrine. Page last updated December 1, 2010. Page accessed February 6, 2016]
  5. ^ Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004 Aug;28(2):140-75. PMID 15276195
  6. ^ Richards BL, Whittle SL, Buchbinder R. Muscle relaxants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008922. PMID 22258993
  7. ^ a b Katzenschlager R, et al. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst Rev. 2003;(2):CD003735. PMID 12804486
  8. ^ a b Ivan Donaldson, C. David Marsden, Susanne Schneider. Marsden's Book of Movement Disorders. Oxford University Press, 2012. ISBN 9780192619112. Page 281
  9. ^ Orphenadrine Citrate Extended release label Revised October 1998
  10. ^ Syvälahti EK, Kunelius R, Laurén L (February 1988). "Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung". Pharmacology & Toxicology. 62 (2): 90–4. doi:10.1111/j.1600-0773.1988.tb01852.x. PMID 3353357. 
  11. ^ Rumore MM, Schlichting DA (February 1985). "Analgesic effects of antihistaminics". Life Sciences. 36 (5): 403–16. doi:10.1016/0024-3205(85)90252-8. PMID 2578597. 
  12. ^ Kornhuber J, Parsons CG, Hartmann S, et al. (1995). "Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies". Journal of Neural Transmission. General Section. 102 (3): 237–46. doi:10.1007/BF01281158. PMID 8788072. 
  13. ^ J Kornhuber; C G Parsons; S Hartmann; W Retz; S Kamolz; J Thome; P Riederer (1995). "Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies". 102 (3): 237–46. doi:10.1007/BF01281158. PMID 8788072. 
  14. ^ Kapur S1, Seeman P. (2002). "NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia". 7 (8): 837–44. doi:10.1038/sj.mp.4001093. PMID 12232776. 
  15. ^ Pubill D, Canudas AM, Pallàs M, et al. (March 1999). "Assessment of the adrenergic effects of orphenadrine in rat vas deferens". The Journal of Pharmacy and Pharmacology. 51 (3): 307–12. doi:10.1211/0022357991772303. PMID 10344632. 
  16. ^ Desaphy JF, Dipalma A, De Bellis M, et al. (April 2009). "Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine". Pain. 142 (3): 225–35. doi:10.1016/j.pain.2009.01.010. PMID 19217209. 
  17. ^ Scholz EP, Konrad FM, Weiss DL, et al. (December 2007). "Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656". Naunyn-Schmiedeberg's Archives of Pharmacology. 376 (4): 275–84. doi:10.1007/s00210-007-0202-6. PMID 17965852. 
  18. ^ Christophe Morice and Camille Wermuth. Ring Transformations. Chapter 9 in The Practice of Medicinal Chemistry, 4th Edition. Eds. Camille Georges Wermuth, David Aldous, Pierre Raboisson, Didier Rognan. Elsevier, 2015 ISBN 9780124172135 pp. 250-251
  19. ^ Camille Georges Wermuth; David Aldous; Pierre Raboisson; Didier Rognan (1 July 2015). The Practice of Medicinal Chemistry. Elsevier Science. pp. 250–251. ISBN 978-0-12-417213-5. 
  20. ^ Walter Sneader (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 405–. ISBN 978-0-471-89979-2. 
  21. ^ Hugo Kubinyi; Gerhard Müller (6 March 2006). Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective. John Wiley & Sons. pp. 54–. ISBN 978-3-527-60402-9. 
  22. ^ FDA listing of Orphenadrine citrate registrations. Page accessed Feb 6, 2016
  23. ^ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 207.
  24. ^ Walter Sneader. Drug Discovery: A History. John Wiley & Sons, 2005 ISBN 9780471899792. Page 405

External links[edit]