Orphenadrine

Structural formula
Structural formula without stereochemistry
General
Non-proprietary name	Orphenadrine
other names	N , N -dimethyl-2 - [(2-methylphenyl) -phenyl-methoxy] -ethanamine ( IUPAC ) ( RS ) - N , N -dimethyl-2 - [(2-methylphenyl) -phenyl-methoxy] -ethanamine (±) - N , N -dimethyl-2 - [(2-methylphenyl) -phenyl-methoxy] -ethanamine 2-methyldiphenhydramine Orphenadrinum ( Latin )
Molecular formula	C 18 H 23 NO C 18 H 23 NO · HCl ( hydrochloride ) C 18 H 23 NO · C 6 H 8 O 7 ( citrate )
External identifiers / databases
CAS number 83-98-7 (racemate) 33425-91-1 ( R ) -orphenadrine 33425-89-7 ( S ) -orphenadrine 341-69-5 (hydrochloride) 4682-36-4 (citrate) EC number 201-509-2 ECHA InfoCard 100.001.372 PubChem 4601 DrugBank DB01173 Wikidata Q3292273
Drug information
ATC code	M03 BC01 (citrate) N04 AB02 (hydrochloride)
Drug class	Anticholinergics Anti-Parkinson drugs (hydrochloride) Muscle relaxant (citrate)
Mechanism of action	Histamine - antagonist at H 1 receptors Antagonist of muscarinic acetylcholine receptors Selective norepinephrine reuptake inhibitor NMDA antagonist Sodium channel inhibitor Potassium channel inhibitor
properties
Molar mass	269.381 g mol −1 305.84 g mol −1 (hydrochloride) 461.50 g mol −1 (citrate)
Physical state	firmly
Melting point	<25 ° C
pK s value	8.91
solubility	113 mg l −1 at 25 ° C
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302-351 P: 281
Toxicological data	125 mg kg −1 ( LD 50 ,  mouse ,  oral ) 33 mg kg −1 ( LD 50 ,  mouse ,  iv ) Hydrochloride: 100 mg kg −1 ( LD 50 ,  mouse ,  oral ) 20 mg kg −1 ( LD 50 ,  mouse ,  iv ) 225 mg kg −1 ( LD 50 ,  rat ,  oral ) 27.5 mg kg −1 ( LD 50 ,  rat ,  iv )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Orphenadrine is a centrally active drug that relaxes the skeletal muscles and is therefore one of the muscle relaxants .

Orphenadrine belongs to the class of H1 antihistamines and is chemically related to diphenhydramine . It is used for the symptomatic treatment of painful tension in the skeletal muscles .

Extraction

Orphenadrine can be obtained by reacting 2-methylbenzhydryl chloride with dimethylaminoethanol .

Stereochemistry

Orphenadrine contains a stereocenter and consists of two enantiomers. This is a racemate , i.e. a 1: 1 mixture of the ( R ) and ( S ) forms:

Enantiomers of orphenadrine
( R ) -Orphenadrine	( S ) -Orphenadrine

history

George Rieveschl led an antihistamine research program at the University of Cincinnati . In 1943, Fred Huber, one of his students, synthesized diphenhydramine . Parke-Davis licensed the patent from George Rieveschl and hired him as head of research from 1947, where he worked on the development of orphenadrin.

Before amantadine and newer drugs, orphenadrine was used in the treatment of Parkinson's disease .

pharmacology

Mechanism of action

Orphenadrine leads to the relaxation of the pathologically increased muscle tone by specifically blocking the support center in the tegmentalized reticular formation , with a simultaneous lack of blocking of the inhibitory center . Normal muscle tone and mobility are not affected. The pain caused by muscle tension and the subsequent reflex reduced blood flow to the muscle tissue are quickly eliminated by Orphenadrin. In addition to the skeletal muscle relaxing effect, orphenadrine has low antihistaminic and local anesthetic as well as mild parasympathicolytic ( anticholinergic ) properties, which are noticeable in the rabbit in an inhibition of saliva secretion. However, this effect is 350 times weaker than that of atropine . In terms of mydriatic activity, orphenadrine is 250 times less effective.

Pharmacokinetics

Orphenadrine is absorbed from the gastrointestinal tract orally. Maximum plasma levels are reached 2 hours after application. The effect of the pure substance lasts for 4–6 hours. Longer administration results in higher plasma levels, which correspond to 2–3 times that of a single dose. After intravenous administration, the maximum is already determined 2 minutes after the injection. Distribution studies show that 90–95% of the substance is bound to plasma protein. The substance is largely metabolized and mainly excreted via the kidneys. Active metabolites are N -demethylorphenadrine and N , N -didemethylorphenadrine.

The bioavailability is between 80 and 90%. The plasma half-life is between 13 and 20 hours.

Contraindications

In myasthenia gravis and children under 16 years orphenadrine should not be taken. Orphenadrine should not be used in patients with narrow-angle glaucoma or prostate problems as it makes them worse. Caution is also required with tachycardia or megacolon . It is not known whether orphenadrine is excreted in breast milk, so it should only be used during breastfeeding after careful consideration.

Side effects

Some of the side effects of orphenadrin are due to its anticholinergic effects.

Frequently

Fatigue, dizziness, blurred vision, nausea, nausea.

Occasionally

Euphoria, nervousness, fear, sleep disorders, confusion, depression, emotional lability, headache, muscle tremors, swallowing and speech disorders, impaired ability to think, appetite and taste disorders, dry eyes, rhinitis , chest pain, stomach pain, dry mouth, constipation , diarrhea, exanthema , Urinary retention, urinary incontinence, discomfort, leg weakness.

Interactions

Amantadine, quinidine , MAOIs, and tricyclic antidepressants can increase the anticholinergic effect. The antiparkinsonian effects of L-dopa can be enhanced by orphenadrine. Taking chlorpromazine at the same time increases the risk of hypothermia . Further interactions of orphenadrine citrate with dextropropoxyphene and thyroxine are described.

Trade names

Orphenadrine is often combined with paracetamol and diclofenac . Less often with celecoxib or mefenamic acid

Monopreparations

Norflex (D), Disipal (I)

Combination preparations

• with Diclofenac: Neodolpasse (A, CZ)
• with paracetamol: Norgesic (A)

Medicines containing orphenadrine are subject to prescription in Germany and Austria .

Individual evidence

1. ↑ Entry on Orphenadrine. In: Römpp Online . Georg Thieme Verlag, accessed on February 10, 2016.
2. ↑ External identifiers or database links for orphenadrine hydrochloride : CAS number: 341-69-5, EC number: 206-435-4, ECHA InfoCard: 100.005.851 , PubChem : 9568 , ChemSpider : 9193 , DrugBank : DB01173 , Wikidata : Q27129640 .
3. ↑ External identifiers or database links for orphenadrine citrate : CAS number: 4682-36-4, EC number: 225-137-5, ECHA InfoCard: 100.022.851 , PubChem : 83823 , ChemSpider : 19620 , DrugBank : DB01173 , Wikidata : Q27107584 .
4. ↑ ^{a b c} Entry on orphenadrine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
5. ↑ ^{a b} data sheet Orphenadrine citrate salt from Sigma-Aldrich , accessed on February 10, 2016 ( PDF ).
6. ↑ ^{a b c d e f} Axel Kleemann, Jürgen Engel, Bernd Kutscher and Dieter Reichert: Pharmaceutical Substances. 4th edition. 2 volumes, Thieme-Verlag, Stuttgart 2000, ISBN 1-58890-031-2 ; online since 2003 with biannual additions and updates.
7. ↑ Overview of the approval of muscle relaxants at KVS Saxony (PDF) accessed in February 2016
8. ^ Kleemann , Engel, Kutscher, Reichert: Pharmaceutical Substances, 4th edition, Thieme-Verlag Stuttgart 2000, page 1504. ISBN 978-1588900319 .
9. ↑ Rote Liste Service GmbH (Ed.): Rote Liste 2017 - drug directory for Germany (including EU approvals and certain medical devices) . Rote Liste Service GmbH, Frankfurt / Main, 2017, edition 57, ISBN 978-3-946057-10-9 , p. 207.
10. ↑ Walter Sneader. Drug Discovery: A History. John Wiley & Sons, 2005 ISBN 9780471899792 . P. 405 .
11. ^ Ivan Donaldson, C. David Marsden, Susanne Schneider. Marsden's Book of Movement Disorders. Oxford University Press, 2012. ISBN 978-0-19261911-2 . Page 281 .
12. ↑ ^{a b c d e} Norflex at medikament.de
13. ↑ Entry on Orphenadrine in the DrugBank of the University of Alberta , accessed November 18, 2019.
14. ↑ JJM Labout, CT Thijssen u. a .: Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man. In: European Journal of Clinical Pharmacology. 21, 1982, p. 343, doi : 10.1007 / BF00637624 .
15. ↑ ^{a b} Neodolpasse at diagnosia, accessed on February 15, 2016.
16. ↑ Orphenadrine Citrate Extended release label version from October 1998.
17. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 511.
18. ↑ Drugs.com International: orphenadrine

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