Orphenadrine Explained

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relaxant that is used to treat muscle pain and to help with motor control in Parkinson's disease, but has largely been superseded by newer drugs.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

Medical use

Orphenadrine is a skeletal muscle relaxant.[1] It is used to relieve pain caused by muscle injuries such as strains and sprains, in combination with rest and physical therapy.[2] 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.[3]

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.[4]

In 2003, a 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cross-over study of orphenadrine vs placebo.[5] Although orphenadrine and other anticholinergics have largely been superseded by other drugs; they have a use in alleviating motor function symptoms, and appear to help about 20% of people with Parkinson's.

Side effects

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, constipation, urine retention, blurred vision, and headache.[2] Its use in Parkinson's is especially limited by these factors.[5]

Orphenadrine is contraindicated in patients with glaucoma, myasthenia gravis, sphincter relaxation disorders, digestive problems such as peptic ulcers, bowel obstruction, or with enlarged prostate, bladder disorders; that is, they should not consume this drug.[6]

Continuous and/or cumulative use of anticholinergic medications, including first-generation antihistamines, is associated with higher risk of cognitive decline and dementia in older people.[7] [8]

Pharmacology

Orphenadrine is known to have these pharmacological properties:

History

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.[19]

Prior to the development of amantadine in the late 1960s and then other drugs, anticholinergics like orphenadrine were the mainstay of Parkinson's treatment.[20]

Formulation

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, compounding powder and by injection for acute use in a hospital setting.[1] [21]

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

The brand names Norflex and Norgesic are formulations of the citrate salt of orphenadrine and Disipal is the hydrochloride salt.[22]

Chemistry

Orphenadrine is a derivative of diphenhydramine with a methyl group added to one of the phenyl rings.[23]

Stereochemistry

Orphenadrine has a chiral center and two enantiomers. When employed as a therapeutic agent, it is typically supplied as the racemate.[24]

Notes and References

  1. Web site: Orphenadrine . Drugs.com international listings . 5 February 2016 .
  2. Web site: Medline Plus . Orphenadrine . 1 December 2010 . 6 February 2016 .
  3. Chou R, Peterson K, Helfand M . Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review . Journal of Pain and Symptom Management . 28 . 2 . 140–75 . August 2004 . 15276195 . 10.1016/j.jpainsymman.2004.05.002 . free .
  4. Richards BL, Whittle SL, Buchbinder R . Muscle relaxants for pain management in rheumatoid arthritis . The Cochrane Database of Systematic Reviews . 1 . CD008922 . January 2012 . 22258993 . 10.1002/14651858.CD008922.pub2 . 205197256 .
  5. Katzenschlager R, Sampaio C, Costa J, Lees A . Anticholinergics for symptomatic management of Parkinson's disease . The Cochrane Database of Systematic Reviews . 2 . CD003735 . 2003 . 2002 . 12804486 . 10.1002/14651858.CD003735 . 8728160 .
  6. Web site: Orphenadrine Citrate Extended release label . https://web.archive.org/web/20231004100741/http://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf . October 1998 . 2023-10-04 . live . 2023-10-04 . U.S. Food and Drug Administration.
  7. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB . 6 . Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study . JAMA Internal Medicine . 175 . 3 . 401–407 . March 2015 . 25621434 . 4358759 . 10.1001/jamainternmed.2014.7663 . Rebecca Hubbard .
  8. Carrière I, Fourrier-Reglat A, Dartigues JF, Rouaud O, Pasquier F, Ritchie K, Ancelin ML . Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study . Archives of Internal Medicine . 169 . 14 . 1317–1324 . July 2009 . 19636034 . 2933398 . 10.1001/archinternmed.2009.229 .
  9. Syvälahti EK, Kunelius R, Laurén L . Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung . Pharmacology & Toxicology . 62 . 2 . 90–4 . February 1988 . 3353357 . 10.1111/j.1600-0773.1988.tb01852.x .
  10. Nurses' Drug Guide 2010
  11. Rumore MM, Schlichting DA . Analgesic effects of antihistaminics . Life Sciences . 36 . 5 . 403–16 . February 1985 . 2578597 . 10.1016/0024-3205(85)90252-8 .
  12. Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P . 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 . 1995 . 8788072 . 10.1007/BF01281158 . 10142765 .
  13. Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P . 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 . 1995 . 8788072 . 10.1007/BF01281158 . 10142765 .
  14. Kapur S, Seeman P . 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 . Molecular Psychiatry . 7 . 8 . 837–44 . 2002 . 12232776 . 10.1038/sj.mp.4001093 . free .
  15. Pubill D, Canudas AM, Pallàs M, Sureda FX, Escubedo E, Camins A, Camarasa J . Assessment of the adrenergic effects of orphenadrine in rat vas deferens . The Journal of Pharmacy and Pharmacology . 51 . 3 . 307–12 . March 1999 . 10344632 . 10.1211/0022357991772303 . 31845784 . free .
  16. Cheng MH, Block E, Hu F, Cobanoglu MC, Sorkin A, Bahar I . Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding . Frontiers in Neurology . 6 . 134 . 2015 . 26106364 . 4460958 . 10.3389/fneur.2015.00134 . free .
  17. Desaphy JF, Dipalma A, De Bellis M, Costanza T, Gaudioso C, Delmas P, George AL, Camerino DC . 6 . Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine . Pain . 142 . 3 . 225–35 . April 2009 . 19217209 . 10.1016/j.pain.2009.01.010 . 11586/128078 . 17830280 .
  18. Scholz EP, Konrad FM, Weiss DL, Zitron E, Kiesecker C, Bloehs R, Kulzer M, Thomas D, Kathöfer S, Bauer A, Maurer MH, Seemann G, Katus HA, Karle CA . 6 . 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 . December 2007 . 17965852 . 10.1007/s00210-007-0202-6 . 20049051 .
  19. Book: Sneader W . Drug Discovery: A History . John Wiley & Sons . 2005 . 978-0-471-89979-2 . 405 .
  20. Book: Donaldson I, Marsden CD, Schneider S . Marsden's Book of Movement Disorders . Oxford University Press . 2012 . 978-0-19-261911-2 . 281 .
  21. Web site: FDA listing of Orphenadrine citrate registrations . United States Food and Drug Administration . 6 February 2016 .
  22. Web site: Disipal Brand of Orphenadrine HCl . Riker .
  23. Book: Morice C, Wermuth C . Ring Transformations. Chapter 9 . The Practice of Medicinal Chemistry . 4th . Wermuth CG, Aldous D, Raboisson P, Rognan D . Camille Georges Wermuth . Elsevier . 2015 . 978-0-12-417213-5 . https://books.google.com/books?id=dtScBAAAQBAJ&pg=PA251 . 250–251 .
  24. Book: Rote Liste Service GmbH (Hrsg.) . Rote Liste 2017 Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte) . Rote Liste Service GmbH . Frankfurt/Main . 2017 . 57 . 978-3-946057-10-9 . 207 .

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