TRIHEXYPHENIDYL

Details

Stereochemistry	RACEMIC
Molecular Formula	C20H31NO
Molecular Weight	301.4662
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(CCN1CCCCC1)(C2CCCCC2)C3=CC=CC=C3

InChI

InChIKey=HWHLPVGTWGOCJO-UHFFFAOYSA-N

InChI=1S/C20H31NO/c22-20(18-10-4-1-5-11-18,19-12-6-2-7-13-19)14-17-21-15-8-3-9-16-21/h1,4-5,10-11,19,22H,2-3,6-9,12-17H2

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00376
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/006773_s036_artane.pdf

Trihexyphenidyl (Artane, Apo-Trihex, Parkin, Pacitane), also known as benzhexol and trihex has been in clinical usage for decades.It is an anticholinergic used in the symptomatic treatment of all etiologic groups of parkinsonism and drug induced extrapyramidal reactions (except tardive dyskinesia). Trihexyphenidyl possesses both anticholinergic and antihistaminic effects, although only the former has been established as therapeutically significant in the management of parkinsonism. Trihexyphenidyl is a selective M1 muscarinic acetylcholine receptor antagonist. It is able to discriminate between the M1 (cortical or neuronal) and the peripheral muscarinic subtypes (cardiac and glandular). Trihexyphenidyl partially blocks cholinergic activity in the CNS, which is responsible for the symptoms of Parkinson's disease. It is also thought to increase the availability of dopamine, a brain chemical that is critical in the initiation and smooth control of voluntary muscle movement. Trihexyphenidyl is indicated for the treatment of parkinson's disease and extrapyramidal reactions caused by drugs.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Muscarinic acetylcholine receptor M1 169 Target ID: CHEMBL216 Sources: http://www.drugbank.ca/drugs/DB00376	Antagonist 2778	1.3 nM [IC50]
Muscarinic acetylcholine receptor M4 86 Target ID: CHEMBL1821 Sources: http://www.drugbank.ca/drugs/DB00376 \| http://www.genome.jp/dbget-bin/www_bget?D00787	Antagonist 2778	6.7 nM [IC50]
Muscarinic acetylcholine receptor M5 62 Target ID: CHEMBL2035 Sources: http://www.drugbank.ca/drugs/DB00376 \| http://www.genome.jp/dbget-bin/www_bget?D00787	Antagonist 2778	10.3 nM [IC50]
Muscarinic acetylcholine receptor M3 159 Target ID: CHEMBL245 Sources: http://www.drugbank.ca/drugs/DB00376 \| http://www.genome.jp/dbget-bin/www_bget?D00787	Antagonist 2778	26.3 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Parkinson's disease 226 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/006773_s036_artane.pdf	Primary		Approved 8429	Trihexyphenidyl hydrochloride Approved Use Trihexyphenidyl HCl tablets are indicated as an adjunct in the treatment of all forms of parkinsonism (postencephalitic, arteriosclerotic, and idiopathic). It is often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa. Additionally, it is indicated for the control of extrapyramidal disorders caused by central nervous system drugs such as the dibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones. Launch Date 1949
Extrapyramidal disorders caused by central nervous system drugs 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/006773_s036_artane.pdf	Secondary		Approved 8429	Trihexyphenidyl hydrochloride Approved Use Trihexyphenidyl HCl tablets are indicated as an adjunct in the treatment of all forms of parkinsonism (postencephalitic, arteriosclerotic, and idiopathic). It is often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa. Additionally, it is indicated for the control of extrapyramidal disorders caused by central nervous system drugs such as the dibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones. Launch Date 1949

C_max

Value	Dose	Co-administered	Analyte	Population
14.9 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3225767/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIHEXYPHENIDYL serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
24.4 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3225767/	5 mg 2 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TRIHEXYPHENIDYL serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
294 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3225767/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIHEXYPHENIDYL serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
334 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3225767/	5 mg 2 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TRIHEXYPHENIDYL serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
10.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3225767/	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIHEXYPHENIDYL serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
8.67 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3225767/	5 mg 2 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TRIHEXYPHENIDYL serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
0.55 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.55 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.55 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	unhealthy, 1-18 years n = 101 Health Status: unhealthy Condition: cerebral palsy with dystonia or/and sialorrhea Age Group: 1-18 years Sex: M+F Population Size: 101 Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	Disc. AE: Constipation, Gastrointestinal disorders... AEs leading to discontinuation/dose reduction: Constipation (2 patients) Gastrointestinal disorders (4 patients) Behaviour disorder (2 patients) Movements involuntary (1 patient) Drowsiness (1 patient) Skin rash (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/
40 mg multiple, oral Higher than recommended Dose: 40 mg Route: oral Route: multiple Dose: 40 mg Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/	unhealthy, 25 years n = 1 Health Status: unhealthy Condition: drug and alcohol dependence Age Group: 25 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/	Other AEs: Dependence... Other AEs: Dependence (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/
5 mg 28 times / day multiple, oral Higher than recommended Dose: 5 mg, 28 times / day Route: oral Route: multiple Dose: 5 mg, 28 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/	unhealthy, 35 years n = 1 Health Status: unhealthy Condition: schizophrenic Age Group: 35 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/	Other AEs: Dependence... Other AEs: Dependence (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/
0.75 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.75 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.75 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/	unhealthy, 4-15 years n = 26 Health Status: unhealthy Condition: cerebral palsy Age Group: 4-15 years Sex: M+F Population Size: 26 Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/	Disc. AE: Chorea, Rash... AEs leading to discontinuation/dose reduction: Chorea (1 patient) Rash (1 patient) Hyperactivity (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/
24 mg 1 times / day multiple, oral (mean) Highest studied dose Dose: 24 mg, 1 times / day Route: oral Route: multiple Dose: 24 mg, 1 times / day Co-administed with:: ethopropazine(350 mg) Sources: https://pubmed.ncbi.nlm.nih.gov/6136938/	unhealthy, adult n = 52 Health Status: unhealthy Condition: torsion dystonia Age Group: adult Sex: unknown Population Size: 52 Sources: https://pubmed.ncbi.nlm.nih.gov/6136938/	Sources: https://pubmed.ncbi.nlm.nih.gov/6136938/
41 mg 1 times / day multiple, oral (mean) Highest studied dose Dose: 41 mg, 1 times / day Route: oral Route: multiple Dose: 41 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6136938/	unhealthy, children n = 23 Health Status: unhealthy Condition: torsion dystonia Age Group: children Sex: unknown Population Size: 23 Sources: https://pubmed.ncbi.nlm.nih.gov/6136938/	Sources: https://pubmed.ncbi.nlm.nih.gov/6136938/
8 mg 1 times / day multiple, oral (mean) Recommended Dose: 8 mg, 1 times / day Route: oral Route: multiple Dose: 8 mg, 1 times / day Co-administed with:: neuroleptic Sources: https://pubmed.ncbi.nlm.nih.gov/3984771/	unhealthy, mean 49.7 years n = 22 Health Status: unhealthy Condition: schizophrenia or mental retardation Age Group: mean 49.7 years Sex: M+F Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/3984771/	Other AEs: Extrapyramidal symptoms... Other AEs: Extrapyramidal symptoms (77%) Sources: https://pubmed.ncbi.nlm.nih.gov/3984771/

AEs

AE	Significance	Dose	Population
Drowsiness	1 patient Disc. AE	0.55 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.55 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.55 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	unhealthy, 1-18 years n = 101 Health Status: unhealthy Condition: cerebral palsy with dystonia or/and sialorrhea Age Group: 1-18 years Sex: M+F Population Size: 101 Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/
Movements involuntary	1 patient Disc. AE	0.55 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.55 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.55 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	unhealthy, 1-18 years n = 101 Health Status: unhealthy Condition: cerebral palsy with dystonia or/and sialorrhea Age Group: 1-18 years Sex: M+F Population Size: 101 Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/
Skin rash	1 patient Disc. AE	0.55 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.55 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.55 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	unhealthy, 1-18 years n = 101 Health Status: unhealthy Condition: cerebral palsy with dystonia or/and sialorrhea Age Group: 1-18 years Sex: M+F Population Size: 101 Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/
Behaviour disorder	2 patients Disc. AE	0.55 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.55 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.55 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	unhealthy, 1-18 years n = 101 Health Status: unhealthy Condition: cerebral palsy with dystonia or/and sialorrhea Age Group: 1-18 years Sex: M+F Population Size: 101 Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/
Constipation	2 patients Disc. AE	0.55 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.55 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.55 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	unhealthy, 1-18 years n = 101 Health Status: unhealthy Condition: cerebral palsy with dystonia or/and sialorrhea Age Group: 1-18 years Sex: M+F Population Size: 101 Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/
Gastrointestinal disorders	4 patients Disc. AE	0.55 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.55 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.55 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/	unhealthy, 1-18 years n = 101 Health Status: unhealthy Condition: cerebral palsy with dystonia or/and sialorrhea Age Group: 1-18 years Sex: M+F Population Size: 101 Sources: https://pubmed.ncbi.nlm.nih.gov/21310336/
Dependence	1 patient	40 mg multiple, oral Higher than recommended Dose: 40 mg Route: oral Route: multiple Dose: 40 mg Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/	unhealthy, 25 years n = 1 Health Status: unhealthy Condition: drug and alcohol dependence Age Group: 25 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/
Dependence	1 patient	5 mg 28 times / day multiple, oral Higher than recommended Dose: 5 mg, 28 times / day Route: oral Route: multiple Dose: 5 mg, 28 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/	unhealthy, 35 years n = 1 Health Status: unhealthy Condition: schizophrenic Age Group: 35 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/6741602/
Chorea	1 patient Disc. AE	0.75 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.75 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.75 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/	unhealthy, 4-15 years n = 26 Health Status: unhealthy Condition: cerebral palsy Age Group: 4-15 years Sex: M+F Population Size: 26 Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/
Hyperactivity	1 patient Disc. AE	0.75 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.75 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.75 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/	unhealthy, 4-15 years n = 26 Health Status: unhealthy Condition: cerebral palsy Age Group: 4-15 years Sex: M+F Population Size: 26 Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/
Rash	1 patient Disc. AE	0.75 mg/kg 1 times / day multiple, oral (mean) Highest studied dose Dose: 0.75 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.75 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/	unhealthy, 4-15 years n = 26 Health Status: unhealthy Condition: cerebral palsy Age Group: 4-15 years Sex: M+F Population Size: 26 Sources: https://pubmed.ncbi.nlm.nih.gov/17690057/
Extrapyramidal symptoms	77%	8 mg 1 times / day multiple, oral (mean) Recommended Dose: 8 mg, 1 times / day Route: oral Route: multiple Dose: 8 mg, 1 times / day Co-administed with:: neuroleptic Sources: https://pubmed.ncbi.nlm.nih.gov/3984771/	unhealthy, mean 49.7 years n = 22 Health Status: unhealthy Condition: schizophrenia or mental retardation Age Group: mean 49.7 years Sex: M+F Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/3984771/

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY523868	https://www.001chemical.com/chem/144-11-6
3B Scientific (Wuhan) Corp	3B3-065679	http://www.3bsc.com/index/pro_info.php?id=104940
Aurora Fine Chemicals LLC	A12.862.769	http://online.aurorafinechemicals.com/info?ID=A12.862.769
Aurum Pharmatech LLC	H2264	http://www.Aurumpharmatech.com/Product/ProductDetails/H2264
BLD Pharm	BD41291	http://www.bldpharm.com/products/144-11-6.html
ChemMol	49416053	http://www.chemmol.com/chemmol/49416053.html
Chemspace	CSSS00020675549	https://chem-space.com/CSSS00020675549
Hairui	HR141293	http://www.hairuichem.com/en/product/144-11-6.html
MolPort	MolPort-001-783-510	https://www.molport.com/shop/molecule-link/MolPort-001-783-510
Molcore	MC523868	https://www.molcore.com/product/144-11-6
OChem	12132	http://www.ocheminc.com/index.php?act=psearch&pid=144T116
Parchem	30212	http://www.parchem.com/chemical-supplier-distributor/Trihexyphenidyl-020212.aspx
Smolecule	S520860	http://www.smolecule.com/products/s520860
THE BioTek	bt-261968	https://www.thebiotek.com/product/inhibitors/bt-261968
Vitas-M Laboratory	BBL024959	http://www.request.vitasmlab.biz/index.php?option=com_search_stk&Itemid=22&stk=BBL024959&?utm_source=pubchem&utm_medium=p_search_link&utm_campaign=pubchem_search&utm_content=pubchem_slink
eNovation Chemicals	D674824	https://www.enovationchem.com/ProductDetails.asp?ProductID=D674824
mcule	MCULE-6065307656	https://mcule.com/MCULE-6065307656/

PubMed

Title	Date	PubMed
Drug-induced extrapyramidal symptoms: their incidence and treatment.	1967 Jan	6016862
Reversal of central anticholinergic syndrome in man by physostigmine.	1968 Nov 25	5755090
Toxic psychosis induced by benzhexol hydrochloride.	1970 Oct 10	5506119
Benzhexol-induced hallucinosis.	1971 Mar 6	5557919
Benzhexol-induced blindness in Parkinson's disease.	1972 Mar 4	5013835
An unusual response to chlorpromazine therapy.	1972 Oct	5077102
Toxic liver injuries.	1973 Aug	4800729
Comparative trial of benzhexol, amantadine, and levodopa in the treatment of Parkinson's disease.	1974 Apr	4838913
Fluphenazine enanthate induced decompensations.	1975	1178807
[Effects of diazepam on six drug-induced locomotor hyperactivities in mice (author's transl)].	1975 Dec 31	129788
[Outcome of Parkinsonism after two years of levodopa plus R04-4602 (author's transl)].	1975 Jul-Aug	785578
Extrapyramidal syndrome with sodium valproate.	1979 Oct 27	391328
Neuroleptic malignant syndrome.	1980 Jul	7387498
Akathisia: an overlooked, distressing, but treatable condition.	1981 Sep	7276921
Malignant neuroleptic syndrome due to haloperidol. (A case report).	1983 Jan	6864584
Trihexyphenidyl dependence.	1984 Jun	6741602
Pharmacological modification of DDT-induced tremor and hyperthermia in rats: distributional factors.	1986	3088650
[Trihexyphenidyl (THP)-induced respiratory dyskinesia].	1986 Feb	3698411
Parkinson's disease and myasthenia gravis: adverse effect of trihexyphenidyl on neuromuscular transmission.	1987 May	3033545
Life-threatening cranial dystonia following trihexyphenidyl withdrawal.	1989	2811895
Schizophrenic psychosis associated with benzhexol (artane) therapy.	1989 Sep	2795088
Risperidone-induced rabbit syndrome.	1998 Sep	9926106
Medication-induced hallucination and cerebral blood flow in Parkinson's disease.	1999 May	10399867
[A case of amoxapine-induced tardive dystonia successfully treated with a low dose anti-cholinergic agent].	2000 Apr	10967655
Effects of selected anticholinergics on acoustic startle response in rats.	2001 Dec	11920928
Increased anticholinergic challenge-induced memory impairment associated with the APOE-epsilon4 allele in the elderly: a controlled pilot study.	2004 Feb	14735126
[Tactile hallucinations induced by trihexyphenidyl in a patient with Parkinson's disease].	2005 Feb	15782612
Acute dystonic reaction to metoclopramide in patients carrying homozygous cytochrome P450 2D6 genetic polymorphisms.	2006 May	16702617
Bipolar affective disorder associated with thenar hypoplasia: is lithium safe?	2010 Jul-Aug	19829091
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

Usual Adult Dose for Extrapyramidal Reaction 4 to 10 mg orally each day. The total daily dose is best tolerated when administered in 2 or three equally separated doses. Usual Adult Dose for Parkinson's Disease Initial: 1 mg/day; increase by 2 mg increments at intervals of 3 to 5 days Usual dose: 6 to 10 mg/day in 3 to 4 divided doses; doses of 12 to 15 mg/day may be required Drug-induced extrapyramidal symptoms: Initial: 1 mg/day; increase as necessary to usual range of 5 to 15 mg/day in 3 to 4 divided doses Use in combination with levodopa: Usual range: 3 to 6 mg/day in divided doses

Route of Administration: Oral

In Vitro Use Guide

Trihexyphenidyl 10, 50, and 100 umol/L depressed the maximal upstroke velocity (Vmax) and the action potential amplitude (APA) of SAP in guinea pig papillary muscles.

Name

Type

Language

TRIHEXYPHENIDYL

Official Name

English

NSC-12268

Code

English

APO-TRIHEX

Brand Name

English

Trihexyphenidyl [WHO-DD]

Common Name

English

TRIHEXYPHENIDYL [VANDF]

Common Name

English

TRIHEXYPHENIDYL [HSDB]

Common Name

English

1-CYCLOHEXYL-1-PHENYL-3-(1-PIPERIDYL)PROPAN-1-OL

Systematic Name

English

trihexyphenidyl [INN]

Common Name

English

BENZHEXOL

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C38149