ORPHENADRINE HYDROCHLORIDE

Details

Stereochemistry	RACEMIC
Molecular Formula	C18H23NO.ClH
Molecular Weight	305.842
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CN(C)CCOC(C1=CC=CC=C1)C2=C(C)C=CC=C2

InChI

InChIKey=UQZKYYIKWZOKKD-UHFFFAOYSA-N

InChI=1S/C18H23NO.ClH/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;1H

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB01173 | https://www.drugs.com/cdi/orphenadrine.html

Orphenadrine is an anticholinergic drug of the ethanolamine antihistamine class used to treat muscle pain and to help with motor control in Parkinson's disease but has largely been superseded by newer drugs. Orphenadrine binds and inhibits both histamine H1 receptors and NMDA receptors. It restores the motor disturbances induced by neuroleptics, in particular, the hyperkinesia. The dopamine deficiency in the striatum increases the stimulating effects of the cholinergic system. This stimulation is counteracted by the anticholinergic effect of orphenadrine. It may have a relaxing effect on skeletal muscle spasms and it has a mood elevating effect. Orphenadrine is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Orphenadrine is an anticholinergic with a predominantly central effect and only a weak peripheral effect. In addition, it has mild antihistaminic and local anesthetic properties. Parkinson's syndrome is the consequence of a disturbed balance between cholinergic and dopaminergic neurotransmission in the basal ganglia caused by a decrease in dopamine. Orphenadrine restores the physiological equilibrium and has a favorable effect on the rigidity and tremor of Parkinson's disease and Parkinsonian syndromes. Adverse reactions of orphenadrine citrate are mainly due to the mild anticholinergic action of orphenadrine citrate and are usually associated with higher dosage. Dryness of the mouth is usually the first adverse effect to appear. When the daily dose is increased, possible adverse effects include tachycardia, palpitation, urinary hesitancy or retention, blurred vision, dilatation of pupils, increased ocular tension, weakness, nausea, vomiting, headache, dizziness, constipation, drowsiness, hypersensitivity reactions, pruritus, hallucinations, agitation, tremor, gastric irritation and rarely urticaria and other dermatoses

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Histamine H1 receptor 315 Target ID: CHEMBL231 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22793499	Antagonist 2778	97.7 µM [IC50]
Glutamate [NMDA] receptor 125 Target ID: CHEMBL2094124 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9464369	Antagonist 2778	6.0 µM [Ki]
Muscarinic acetylcholine receptor 160 Target ID: CHEMBL2094109 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3353357	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Musculoskeletal pain 10 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf	Primary		Approved 8429	DISIPAL Approved Use Orphenadrine citrate extended-release tablets are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Launch Date 1957
Quinine-resistant leg cramps 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Prntlbl.pdf	Primary		Approved 8429	DISIPAL Approved Use Orphenadrine citrate extended-release tablets are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. Launch Date 1957

C_max

Value	Dose	Co-administered	Analyte	Population
41.89 ng/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
49.19 ng/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
1739.15 ng × h/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1772.44 ng × h/mL REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
21.02 h REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
22.29 h REVIEW https://www.accessdata.fda.gov/drugsatfda_docs/anda/99/40249_Orphenadrine%20Citrate_Bioeqr.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ORPHENADRINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
7% EXPERIMENT https://www.sciencedirect.com/science/article/pii/S0021967307003342?via%3Dihub			ORPHENADRINE plasma	Homo sapiens

Doses

Dose	Population	Adverse events
500 mg 1 times / day steady, oral Highest studied dose Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/1220958	unhealthy, adult Health Status: unhealthy Condition: depression Age Group: adult Sources: https://pubmed.ncbi.nlm.nih.gov/1220958	Sources: https://pubmed.ncbi.nlm.nih.gov/1220958
2 g single, intramuscular Overdose Dose: 2 g Route: intramuscular Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
2 g single, intravenous Overdose Dose: 2 g Route: intravenous Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	Other AEs: Toxic reaction (NOS)... Other AEs: Toxic reaction (NOS) (grade 5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf

AEs

AE	Significance	Dose	Population
Toxic reaction (NOS)	grade 5	2 g single, intramuscular Overdose Dose: 2 g Route: intramuscular Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
Toxic reaction (NOS)	grade 5	2 g single, intravenous Overdose Dose: 2 g Route: intravenous Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf
Toxic reaction (NOS)	grade 5	2 g single, oral Overdose Dose: 2 g Route: oral Route: single Dose: 2 g Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/012157s028lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/013055s021lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 CYP1A2 1524 CYP2A6 707 CYP2C19 1478 OCT2 647 OCT1 512 MATE1 306 MATE2 263		CYP2B 32

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2A6 739	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2C19 1553	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP3A4 1925	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	partial
CYP2B6 1001	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
CYP2C9 1819	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
CYP2D6 1891	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/25/3/390.long	strong
MATE1 308	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 65 uM]
MATE2 263	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 >100 uM]
OCT1 543	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	weak [IC50 >100 uM]
OCT2 648	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257218/	yes [IC50 2.5 uM]
CYP2B 40	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/12813002/	yes

Sourcing

Vendor/Aggregator	ID	URL
Aurora Fine Chemicals LLC	K02.874.612	http://online.aurorafinechemicals.com/info?ID=K02.874.612
BLD Pharm	BD63442	http://www.bldpharm.com/products/83-98-7.html
ChemMol	99164358	http://www.chemmol.com/chemmol/99164358.html
Chemspace	CSSB00020618959	https://chem-space.com/CSSB00020618959
Clearsynth	CS-P-00468	https://www.clearsynth.com/en/CSP00468.html
Smolecule	S603082	https://www.smolecule.com/products/s603082
THE BioTek	bt-364984	https://www.thebiotek.com/product/others/bt-364984
eNovation Chemicals	D111469	https://www.enovationchem.com/ProductDetails.asp?ProductID=D111469
iChemical	EBD71118	http://www.ichemical.com/products/83-98-7.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs
mcule	MCULE-7320950210	https://mcule.com/MCULE-7320950210/

PubMed

Title	Date	PubMed

Prochlorperazine in childhood: side-effects.	1977	216517
Reversal of orphenadrine-induced ventricular tachycardia with physostigmine.	1991 Nov-Dec	1787292
Analgesic effects of low-dose intravenous orphenadrine in the state of capsaicin hyperalgesia. A randomised, placebo-controlled, double-blind cross-over study using laser somatosensory evoked potentials obtained from capsaicin-irritated skin in healthy volunteers.	2004	15553107
Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review.	2004 Aug	15276195
Drug-drug interactions of Z-338, a novel gastroprokinetic agent, with terfenadine, comparison with cisapride, and involvement of UGT1A9 and 1A8 in the human metabolism of Z-338.	2004 Aug 23	15306208
Validated semiquantitative/quantitative screening of 51 drugs in whole blood as silylated derivatives by gas chromatography-selected ion monitoring mass spectrometry and gas chromatography electron capture detection.	2004 Jul 5	15171931
NMDA receptor in nucleus accumbens is implicated in morphine withdrawal in rats.	2004 Nov	15662845
Rhythm-specific pharmacological modulation of subthalamic activity in Parkinson's disease.	2004 Oct	15380487
Alternatives to levodopa in the initial treatment of early Parkinson's disease.	2005	16156677
Comparison of the analgesic effects of a fixed-dose combination of orphenadrine and diclofenac (Neodolpasse) with its single active ingredients diclofenac and orphenadrine: a placebo-controlled study using laser-induced somatosensory-evoked potentials from capsaicin-induced hyperalgesic human skin.	2005	15991879
Primary chemotherapy with gemcitabine, epirubicin and taxol (GET) in operable breast cancer: a phase II study.	2005 Aug 22	16052214
Metabolism of territrem B and C in liver microsomes from 14-wk-old Wistar rats is catalyzed by cytochrome P-450 3A.	2005 Feb 27	15799453
Dimemorfan N-demethylation by mouse liver microsomal cytochrome P450 enzymes.	2005 Jul 1	15936348
Benzodiazepine prescribing behaviour and attitudes: a survey among general practitioners practicing in northern Thailand.	2005 Jun 23	15975145
Simultaneous determination of ten antihistamine drugs in human plasma using pipette tip solid-phase extraction and gas chromatography/mass spectrometry.	2006	16419026
Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous ipriflavone in rats.	2006 Apr	16597362
Catanionic mixtures involving a drug: a rather general concept that can be utilized for prolonged drug release from gels.	2006 Apr	16498573
Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous omeprazole in rats.	2006 Jul	16586464
Pharmacokinetic study of orphenadrine using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).	2006 Jul 24	16580894
Torsades de pointes in congenital long QT syndrome following low-dose orphenadrine.	2006 May	16700864
A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer.	2006 May 24	16723016
Epirubicin/paclitaxel/etoposide in extensive-stage small-cell lung cancer: a phase I-II study.	2006 May 8	16622468
Efficacy and safety of combined piroxicam, dexamethasone, orphenadrine, and cyanocobalamin treatment in mandibular molar surgery.	2006 Sep	16981050
Acute adverse cutaneous reaction after the concomitant use of venlafaxine and orphenadrine citrate plus paracetamol in a depressed patient.	2006 Sep	16922966
Propofol metabolism is enhanced after repetitive ketamine administration in rats: the role of cytochrome P-450 2B induction.	2006 Sep	16845130
Characterization of antihistamine-human serum protein interactions by capillary electrophoresis.	2007 Apr 20	17339039
Evaluation of enantioselective binding of basic drugs to plasma by ACE.	2007 Aug	17661317
Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656.	2007 Dec	17965852
Enantiomeric quality control of antihistamines in pharmaceuticals by affinity electrokinetic chromatography with human serum albumin as chiral selector.	2007 Jun 5	17512827
Effect of warnings in a medical journal on the use of orphenadrine.	2008 Aug	18462287
Pharmacokinetic, metabolism and withdrawal time of orphenadrine in camels (Camelus dromedarius) after intravenous administration.	2008 Dec	18321539
Genetic and chemical modifiers of a CUG toxicity model in Drosophila.	2008 Feb 13	18270582
Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU.	2008 Jan	18088504
[Diclofenac/orphenadrine as a combined analgetic in post-operative relief of pain].	2008 Sep 28	18805773
Concordant up-regulation of cytochrome P450 Cyp3a11, testosterone oxidation and androgen receptor expression in mouse brain after xenobiotic treatment.	2009 Apr	19226368
Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine.	2009 Apr	19217209
The use of antipsychotic and anticholinergic antiparkinson drugs in Norway after the withdrawal of orphenadrine.	2009 Aug	19694744
Evaluation of luciferin-isopropyl acetal as a CYP3A4 substrate for human hepatocytes: effects of organic solvents, cytochrome P450 (P450) inhibitors, and P450 inducers.	2009 Aug	19451401
Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism.	2009 Jan	19126296
Fixed drug eruption resulting from fluconazole use: a case report.	2009 Jul 6	19830193
Trends in the molecular pathogenesis and clinical therapeutics of common neurodegenerative disorders.	2009 Jun 3	19582217
Physiological and pathological role of alpha-synuclein in Parkinson's disease through iron mediated oxidative stress; the role of a putative iron-responsive element.	2009 Mar	19399246
Drugs associated with more suicidal ideations are also associated with more suicide attempts.	2009 Oct 2	19798416
Orphenadrinium picrate picric acid.	2010 Feb 24	21580426
(2-Methyl-phen-yl)(phen-yl)methanol.	2010 Jul 31	21588424
Pharmacologic management of chronic pain.	2010 Jun	20556211
7-Benzyloxyresorufin-O-dealkylase activity as a marker for measuring cytochrome P450 CYP3A induction in mouse liver.	2010 Mar 1	19903449
Opiate sparing effect of fixed combination of diclophenac and orphenadrine after unilateral total hip arthroplasty: A double-blind, randomized, placebo-controlled, multi-centre clinical trial.	2010 Nov	20890791
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003

Patents

Sample Use Guides

In Vivo Use Guide

Acute musculoskeletal conditions: 100 mg orally twice a day (morning and evening) or 60 mg by intramuscular or intravenous injection. May repeat every 12 hours. Quinine-resistant leg cramps: 100 mg orally at bedtime.

Route of Administration: Other

In Vitro Use Guide

An aliquot (400 mkl) of the brain membrane suspension (0.14 mg of protein), 100 mkl of (-)3H-QNB (0.95 nM) (specific activity 46 Ci/mmol), and 50 mk1 of the competing drugs at various concentrations were preincubated for 10 min. and thereafter incubated for 60 min. at 25C in 50 mM Tris-HC1 buffer (PH 7.4). When binding to heart and lung membranes was studied, 500 nkl of homogenate (protein contents were 0.58 mg and 0.54 mg of rat heart and lung tissue and 0.63 mg of guinea pig lung tissue was added to tubes containing 500 mkl of 50 mM Tris-HC1 buffer (PH 7.4), 100 mk1 of (-)3H-QNB (final concentration 0.4 nM) and 100 mkl of buffer (total binding) or unlabeled Orphenadrine.

Name

Type

Language

ORPHENADRINE HYDROCHLORIDE

Common Name

English

ORPHENADRINE HYDROCHLORIDE [EP IMPURITY]

Common Name

English

Orphenadrine hydrochloride [WHO-DD]

Common Name

English

ORPHENADRINE (CHLORIDE)

Common Name

English

ORPHENADRINE HYDROCHLORIDE [EP MONOGRAPH]

Common Name

English

ORPHENADRINE HYDROCHLORIDE [MART.]

Common Name

English

MEPHENAMIN

Brand Name

English

NSC-82357

Code

English

ORPHENADRINE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

ORPHENADRINE HYDROCHLORIDE [VANDF]

Common Name

English

DISIPAL

Brand Name

English

ORPHENADRINE HCL

Common Name

English

Classification Tree Code System Code

WHO-VATC

QN04AB02