Orphenadrine

Orphenadrine
Names
Trade namesGeneric; many brands[1]
Other namesOrphenadrine hydrochloride
IUPAC name
  • (RS)-N,N-Dimethyl-2-[(2-methylphenyl)-phenyl-methoxy]-ethanamine
Clinical data
Drug classAnticholinergic, antihistamine[2]
Main usesMuscle pain, Parkinsonism[2][3]
Side effectsDry mouth, fast heart rate, urinary retention, blurry vision, nausea, sleepiness, constipation[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B2
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth, intravenous, intramuscular
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa682162
    Legal
    Legal status
    • AU: S4 (Prescription only)
    • CA: OTC
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetics
    Bioavailability90%
    Protein binding95%
    MetabolismLiver demethylation
    Elimination half-life13-20 hours[4]
    ExcretionKidney and biliary
    Chemical and physical data
    FormulaC18H23NO
    Molar mass269.388 g·mol−1
    3D model (JSmol)
    SMILES
    • O(CCN(C)C)C(c1ccccc1)c2ccccc2C
    InChI
    • InChI=1S/C18H23NO/c1-15-9-7-8-12-17(15)18(20-14-13-19(2)3)16-10-5-4-6-11-16/h4-12,18H,13-14H2,1-3H3 checkY
    • Key:QVYRGXJJSLMXQH-UHFFFAOYSA-N checkY

    Orphenadrine, sold under many brand names, is a medication used to treat muscle pain including low back pain, and Parkinsonism.[2][3] It is taken by mouth or by injection.[2]

    Common side effects include dry mouth, fast heart rate, urinary retention, blurry vision, nausea, sleepiness, and constipation.[2] Other side effects may include anaphylaxis.[2] Safety in pregnancy is unclear.[2] It is an anticholinergic and antihistamine.[2] How it works is not entirely clear.[2]

    Orphenadrine was developed in the 1940s and approved for medical use in the United States in 1957.[5][2] It is available as a generic medication.[3] In the United Kingdom 30 doses of 50 mg cost the NHS about £56 as of 2021.[3] In the United States this amount costs less than 20 USD.[6]

    Medical use

    Orphenadrine is used to relieve pain caused by muscle injuries like strains and sprains in combination with rest and physical therapy.[7] 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.[8]

    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.[9]

    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.[10] 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.[11]

    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.[7] Its use in Parkinson's is especially limited by these factors.[10]

    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.[12]

    Pharmacology

    Orphenadrine is known to have this pharmacology:

    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.[22]

    Prior to the development of amantadine in the late 1960s and then other drugs, anticholinergics like orphenadrine were the mainstay of Parkinson's treatment.[11]

    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]

    Enantiomers

    (R)-orphenadrine
    CAS number: 33425-91-1
    (S)-orphenadrine
    CAS number: 33425-89-7

    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][25]

    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.[26]

    References

    1. 1 2 3 "Orphenadrine". Drugs.com international listings. Archived from the original on 5 March 2016. Retrieved 5 February 2016.
    2. 1 2 3 4 5 6 7 8 9 10 11 "Orphenadrine Monograph for Professionals". Drugs.com. Archived from the original on 11 July 2021. Retrieved 9 November 2021.
    3. 1 2 3 4 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 431. ISBN 978-0857114105.
    4. ↑ 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. S2CID 24631265. Archived from the original on 2021-10-26. Retrieved 2021-10-08.
    5. ↑ Deer, Timothy R.; Pope, Jason E.; Lamer, Tim J.; Provenzano, David (1 August 2019). Deer's Treatment of Pain: An Illustrated Guide for Practitioners. Springer. p. 185. ISBN 978-3-030-12281-2. Archived from the original on 9 November 2021. Retrieved 9 November 2021.
    6. ↑ "Orphenadrine Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 12 July 2021. Retrieved 9 November 2021.
    7. 1 2 "Orphenadrine". Medline Plus. 1 December 2010. Archived from the original on 7 February 2016. Retrieved 6 February 2016.
    8. ↑ Chou R, Peterson K, Helfand M (August 2004). "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. doi:10.1016/j.jpainsymman.2004.05.002. PMID 15276195.
    9. ↑ Richards BL, Whittle SL, Buchbinder R (January 2012). "Muscle relaxants for pain management in rheumatoid arthritis". The Cochrane Database of Systematic Reviews. 1: CD008922. doi:10.1002/14651858.CD008922.pub2. PMID 22258993. S2CID 205197256. Archived from the original on 2021-10-26. Retrieved 2021-10-08.
    10. 1 2 Katzenschlager R, Sampaio C, Costa J, Lees A (2003). "Anticholinergics for symptomatic management of Parkinson's disease". The Cochrane Database of Systematic Reviews (2): CD003735. doi:10.1002/14651858.CD003735. PMID 12804486.
    11. 1 2 Donaldson I, Marsden CD, Schneider S (2012). Marsden's Book of Movement Disorders. Oxford University Press. p. 281. ISBN 978-0-19-261911-2. Archived from the original on 2016-02-10. Retrieved 2021-10-08.
    12. ↑ Orphenadrine Citrate Extended release label Archived 2021-04-08 at the Wayback Machine Revised October 1998
    13. ↑ 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.
    14. ↑ Nurses' Drug Guide 2010
    15. 1 2 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.
    16. ↑ Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P (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. S2CID 10142765. Archived from the original on 2021-10-26. Retrieved 2021-10-08.
    17. ↑ Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P (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. S2CID 10142765. Archived from the original on 2021-10-26. Retrieved 2021-10-08.
    18. ↑ Kapur S, 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". Molecular Psychiatry. 7 (8): 837–44. doi:10.1038/sj.mp.4001093. PMID 12232776.
    19. ↑ Pubill D, Canudas AM, Pallàs M, Sureda FX, Escubedo E, Camins A, Camarasa J (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. S2CID 31845784. Archived from the original on 2021-10-26. Retrieved 2021-10-08.
    20. ↑ Desaphy JF, Dipalma A, De Bellis M, Costanza T, Gaudioso C, Delmas P, 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. S2CID 17830280. Archived from the original on 2019-11-16. Retrieved 2021-10-08.
    21. ↑ Scholz EP, Konrad FM, Weiss DL, Zitron E, Kiesecker C, Bloehs R, 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. S2CID 20049051. Archived from the original on 2021-10-26. Retrieved 2021-10-08.
    22. ↑ Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 405. ISBN 978-0-471-89979-2. Archived from the original on 2016-02-10. Retrieved 2021-10-08.
    23. ↑ Morice C, Wermuth C (2015). "Ring Transformations. Chapter 9". In Wermuth CG, Aldous D, Raboisson P, Rognan D (eds.). The Practice of Medicinal Chemistry (4th ed.). Elsevier. pp. 250–251. ISBN 978-0-12-417213-5. Archived from the original on 2016-02-10. Retrieved 2021-10-08.
    24. ↑ Rote Liste Service GmbH (Hrsg.) (2017). Rote Liste 2017 Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Vol. 57. Frankfurt/Main: Rote Liste Service GmbH. p. 207. ISBN 978-3-946057-10-9.
    25. ↑ "FDA listing of Orphenadrine citrate registrations". United States Food and Drug Administration. Archived from the original on 26 October 2021. Retrieved 6 February 2016.
    26. ↑ "Disipal Brand of Orphenadrine HCl". Riker. Archived from the original on 2016-08-18. Retrieved 2021-10-08.
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