orphenadrine

{{Drugbox

| verifiedrevid = 462265971

| IUPAC_name = (RS)-N,N-Dimethyl-2-[(2-methylphenyl)-phenyl-methoxy]-ethanamine

| image = Orphenadrine.svg

| image_class = skin-invert-image

| tradename = Generic; many brand names

| Drugs.com = {{drugs.com|monograph|norflex}}

| MedlinePlus = a682162

| pregnancy_AU = B2

| pregnancy_US = C

| legal_AU = S4

| legal_CA = OTC

| legal_NZ = Prescription only

| legal_UK = POM

| legal_US = Rx-only

| routes_of_administration = Oral, intravenous, intramuscular

| bioavailability = 90%

| protein_bound = 95%

| metabolism = Hepatic demethylation

| elimination_half-life = 13–20 hours{{cite journal | vauthors = Labout JJ, Thijssen C, Keijser GG, Hespe W | title = Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man | journal = European Journal of Clinical Pharmacology | volume = 21 | issue = 4 | pages = 343–50 | year = 1982 | pmid = 7056281 | doi = 10.1007/BF00637624 | s2cid = 24631265 }}

| excretion = Renal and biliary

| IUPHAR_ligand = 7251

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 83-98-7

| ATC_prefix = M03

| ATC_suffix = BC01

| ATC_supplemental = {{ATC|N04|AB02}}

| PubChem = 4601

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01173

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4440

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = AL805O9OG9

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08305

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 7789

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 900

| C = 18

| H = 23

| N = 1

| O = 1

| smiles = O(CCN(C)C)C(c1ccccc1)c2ccccc2C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = QVYRGXJJSLMXQH-UHFFFAOYSA-N

}}

Orphenadrine (sold under many brand names){{cite web | url = https://www.drugs.com/international/orphenadrine.html | work = Drugs.com international listings | title = Orphenadrine | access-date = 5 February 2016 }} 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relaxant that is used to treat muscle pain and to help with motor control in Parkinson's disease, but has largely been superseded by newer drugs.{{citation needed|date=August 2022}} It is considered a dirty drug due to its multiple mechanisms of action in different pathways.{{citation needed|date=August 2022}} It was discovered and developed in the 1940s.

Medical use

Orphenadrine is a skeletal muscle relaxant. It is used to relieve pain caused by muscle injuries such as strains and sprains, in combination with rest and physical therapy.{{cite web | work = Medline Plus | url = https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682162.html | title = Orphenadrine | date = 1 December 2010 | access-date = 6 February 2016 }} 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.{{cite journal | vauthors = Chou R, Peterson K, Helfand M | title = Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review | journal = Journal of Pain and Symptom Management | volume = 28 | issue = 2 | pages = 140–75 | date = August 2004 | pmid = 15276195 | doi = 10.1016/j.jpainsymman.2004.05.002 | doi-access = free }}

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.{{cite journal | vauthors = Richards BL, Whittle SL, Buchbinder R | title = Muscle relaxants for pain management in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD008922 | date = January 2012 | pmid = 22258993 | doi = 10.1002/14651858.CD008922.pub2 | s2cid = 205197256 | url = https://semanticscholar.org/paper/003c071b2e52403938b6a16031f1b6c93d95b8a3 | pmc = 11702505 }}

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.{{cite journal | vauthors = Katzenschlager R, Sampaio C, Costa J, Lees A | title = Anticholinergics for symptomatic management of Parkinson's disease | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD003735 | date = 2003 | volume = 2002 | pmid = 12804486 | doi = 10.1002/14651858.CD003735 | pmc = 8728160 }} 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. Its use in Parkinson's is especially limited by these factors.

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.{{Cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf |title=Orphenadrine Citrate Extended release label |archive-url=https://web.archive.org/web/20231004100741/http://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf |date=October 1998 |access-date=2023-10-04 |url-status=live |archive-date=2023-10-04 |website=U.S. Food and Drug Administration}}

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.{{cite journal | vauthors = Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB | display-authors = 6 | title = Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study | journal = JAMA Internal Medicine | volume = 175 | issue = 3 | pages = 401–407 | date = March 2015 | pmid = 25621434 | pmc = 4358759 | doi = 10.1001/jamainternmed.2014.7663 | author5-link = Rebecca Hubbard }}{{cite journal | vauthors = Carrière I, Fourrier-Reglat A, Dartigues JF, Rouaud O, Pasquier F, Ritchie K, Ancelin ML | title = Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study | journal = Archives of Internal Medicine | volume = 169 | issue = 14 | pages = 1317–1324 | date = July 2009 | pmid = 19636034 | pmc = 2933398 | doi = 10.1001/archinternmed.2009.229 }}

Pharmacology

Orphenadrine is known to have these pharmacological properties:

Nonselective mACh receptor antagonist (anticholinergic, 58% as potent as atropine){{cite journal | vauthors = Syvälahti EK, Kunelius R, Laurén L | title = Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung | journal = Pharmacology & Toxicology | volume = 62 | issue = 2 | pages = 90–4 | date = February 1988 | pmid = 3353357 | doi = 10.1111/j.1600-0773.1988.tb01852.x }} Various monographs and package inserts, nursing manuals, journal articles and so forth have proposed the theory that this anticholinergic (atropine-like) activity, NMDA antagonism and possible local anaesthetic and miscellaneous analgesic effects may be the reason for orphenadrine's efficacy against muscle and other pain.Nurses' Drug Guide 2010 {{full|date=September 2019}} These reasons are behind the use of orphenadrine and other drugs of a number of types which are used with paracetamol, aspirin, naproxen, and similar agents with or without opioid analgesics to more effectively manage pain of various types.{{cite journal | vauthors = Rumore MM, Schlichting DA | title = Analgesic effects of antihistaminics | journal = Life Sciences | volume = 36 | issue = 5 | pages = 403–16 | date = February 1985 | pmid = 2578597 | doi = 10.1016/0024-3205(85)90252-8 }}
H₁ receptor antagonist (antihistamine)
NMDA receptor antagonist{{cite journal | vauthors = Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P | title = Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies | journal = Journal of Neural Transmission. General Section | volume = 102 | issue = 3 | pages = 237–46 | year = 1995 | pmid = 8788072 | doi = 10.1007/BF01281158 | s2cid = 10142765 }} (K_i value of {{nobr|6.0 ± 0.7 μM}}, one hundred times less potent than phencyclidine, which binds with a K_i of 59 nM){{cite journal | vauthors = Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P | title = Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies | journal = Journal of Neural Transmission. General Section | volume = 102 | issue = 3 | pages = 237–46 | year = 1995 | pmid = 8788072 | doi = 10.1007/BF01281158 | s2cid = 10142765 }}{{cite journal | vauthors = Kapur S, Seeman P | title = 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 | journal = Molecular Psychiatry | volume = 7 | issue = 8 | pages = 837–44 | year = 2002 | pmid = 12232776 | doi = 10.1038/sj.mp.4001093 | doi-access = free }}
NDRI (norepinephrine and dopamine reuptake inhibitor){{cite journal | vauthors = Pubill D, Canudas AM, Pallàs M, Sureda FX, Escubedo E, Camins A, Camarasa J | title = Assessment of the adrenergic effects of orphenadrine in rat vas deferens | journal = The Journal of Pharmacy and Pharmacology | volume = 51 | issue = 3 | pages = 307–12 | date = March 1999 | pmid = 10344632 | doi = 10.1211/0022357991772303 | s2cid = 31845784 | doi-access = free }}{{cite journal | vauthors = Cheng MH, Block E, Hu F, Cobanoglu MC, Sorkin A, Bahar I | title = Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding | journal = Frontiers in Neurology | volume = 6 | pages = 134 | year = 2015 | pmid = 26106364 | pmc = 4460958 | doi = 10.3389/fneur.2015.00134 | doi-access = free }}
Na_v1.7, Na_v1.8, and Na_v1.9 sodium channel blocker{{cite journal | vauthors = Desaphy JF, Dipalma A, De Bellis M, Costanza T, Gaudioso C, Delmas P, George AL, Camerino DC | display-authors = 6 | title = Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine | journal = Pain | volume = 142 | issue = 3 | pages = 225–35 | date = April 2009 | pmid = 19217209 | doi = 10.1016/j.pain.2009.01.010 | hdl = 11586/128078 | s2cid = 17830280 | url = https://zenodo.org/record/896063 }}
HERG potassium channel blocker{{cite journal | vauthors = 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 | display-authors = 6 | title = Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656 | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 376 | issue = 4 | pages = 275–84 | date = December 2007 | pmid = 17965852 | doi = 10.1007/s00210-007-0202-6 | s2cid = 20049051 }}

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.{{cite book | vauthors = Sneader W | title = Drug Discovery: A History | publisher = John Wiley & Sons | date = 2005 | isbn = 978-0-471-89979-2 | url = https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA405 | page = 405 }}

Prior to the development of amantadine in the late 1960s and then other drugs, anticholinergics like orphenadrine were the mainstay of Parkinson's treatment.{{cite book | vauthors = Donaldson I, Marsden CD, Schneider S | title = Marsden's Book of Movement Disorders | publisher = Oxford University Press | date = 2012 | isbn = 978-0-19-261911-2 | url = https://books.google.com/books?id=g815isikVSAC&pg=PA281 | page = 281 }}

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.{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=ORPHENADRINE%20CITRATE | title = FDA listing of Orphenadrine citrate registrations | publisher = United States Food and Drug Administration | access-date = 6 February 2016 }}

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

The brand names Norflex and Norgesic are formulations of the citrate salt of orphenadrine and Disipal is the hydrochloride salt.{{cite web | title = Disipal Brand of Orphenadrine HCl | publisher = Riker | url = http://www.decodog.com/inven/MD/md30554.jpg}}

Chemistry

Orphenadrine is a derivative of diphenhydramine with a methyl group added to one of the phenyl rings.{{cite book | vauthors = Morice C, Wermuth C | chapter = Ring Transformations. Chapter 9 | title = The Practice of Medicinal Chemistry | edition = 4th | veditors = Wermuth CG, Aldous D, Raboisson P, Rognan D | editor-link1 = Camille Georges Wermuth | publisher = Elsevier | date = 2015 | isbn = 978-0-12-417213-5 | chapter-url = https://books.google.com/books?id=dtScBAAAQBAJ&pg=PA251 | pages = 250–251 }}

=Stereochemistry=

Orphenadrine has a chiral center and two enantiomers. When employed as a therapeutic agent, it is typically supplied as the racemate.{{cite book | author = Rote Liste Service GmbH (Hrsg.) | title = Rote Liste 2017 Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte) | publisher = Rote Liste Service GmbH | location = Frankfurt/Main | date = 2017 | volume = 57 | isbn = 978-3-946057-10-9 | pages = 207 }}

class="wikitable" style="text-align:center"
colspan="2"\|Enantiomers
File:(R)-Orphenadrin Structural Formula V1.svg (R)-orphenadrine CAS number: 33425-91-1 \| File:(S)-Orphenadrin Structural Formula V1.svg (S)-orphenadrine CAS number: 33425-89-7

class="wikitable" style="text-align:center"

colspan="2"|Enantiomers

File:(R)-Orphenadrin Structural Formula V1.svg
(R)-orphenadrine
CAS number: 33425-91-1

| File:(S)-Orphenadrin Structural Formula V1.svg
(S)-orphenadrine
CAS number: 33425-89-7