An official website of the United States government

Trihexyphenidyl

PubChem CID
5572
Structure
Trihexyphenidyl_small.png
Trihexyphenidyl_3D_Structure.png
Molecular Formula
Synonyms
  • trihexyphenidyl
  • Benzhexol
  • 144-11-6
  • Triphenidyl
  • Trihexyphenidyle
Molecular Weight
301.5 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Trihexyphenidyl is an amine.
Trihexyphenidyl is a centrally acting muscarinic antagonist used for treatment of parkinsonism and drug-induced extrapyramidal disorders. Its discovery was published in 1949 in a study looking for drugs with antispasmodic activity. Trihexyphenidyl is rarely used in the treatment of parkinsonism, and is not a first line treatment due to significant adverse effects. It has largely been replaced by drugs such as [levodopa]. Trihexyphenidyl was granted FDA approval on 13 May 1949.
Trihexyphenidyl is an oral anticholinergic agent used predominantly in the symptomatic therapy of Parkinson disease and movement disorders. Trihexyphenidyl has not been associated with serum enzyme elevations during treatment, but has been implicated in rare cases of acute liver injury.
See also: Trihexyphenidyl Hydrochloride (has salt form); Trihexyphenidyl, (R)- (annotation moved to).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Trihexyphenidyl.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

1-cyclohexyl-1-phenyl-3-piperidin-1-ylpropan-1-ol
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

HWHLPVGTWGOCJO-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C1CCC(CC1)C(CCN2CCCCC2)(C3=CC=CC=C3)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C20H31NO
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

144-11-6
40520-25-0

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 NSC Number

2.3.15 PharmGKB ID

2.3.16 Pharos Ligand ID

2.3.17 RXCUI

2.3.18 Wikidata

2.3.19 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Apo Trihex
  • Apo-Trihex
  • ApoTrihex
  • Artane
  • Benzhexol
  • Cyclodol
  • Hipokinon
  • Parkinane
  • Parkopan
  • Trihexane
  • Trihexidyl Hydrochloride
  • Trihexyphenidyl
  • Trihexyphenidyl Hydrochloride
  • Trihexyphenidyl Hydrochloride Elixir

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
301.5 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
4.5
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
301.240564612 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
301.240564612 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
23.5 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
22
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
314
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Melting Point

115 °C
WHO International Pharmacopoeia 6th Edition, 2016
114 °C
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-130
258.5 °C

3.2.3 Solubility

Crystals; decomp at 258.5 °C; pH of 1% aq soln 5.5-6.0; solubility (g/100 mL): water at 25 °C 1.0, alcohol 6, chloroform 5; more soluble in methanol; very slightly soluble in ether, benzene /Hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1665
3.14e-03 g/L

3.2.4 LogP

4.49
SANGSTER (1993)
log Kow = 4.49
Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1993)
4.5

3.2.5 Dissociation Constants

pKa
8.7
Zhao et al, 2004

3.2.6 Collision Cross Section

175.1 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

173.72 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

169.71 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

178.37 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.7 Kovats Retention Index

Standard non-polar
2236 , 2226 , 2226 , 2240 , 2260 , 2240.6 , 2254.2 , 2226 , 2230 , 2233 , 2236 , 2236 , 2236 , 2211 , 2250 , 2275 , 2275 , 2280
Semi-standard non-polar
2237.9

3.2.8 Other Experimental Properties

White or slightly off white, crystalline powder ... very faint odor /Hydrochloride/
FDA; Center for Drug Evaluation and Research. Application Number: 40254. Trihexyphenidyl Hydrochloride Tablets USP. IN-153. Rev 8/97. Washington, DC: Food Drug Admin. Available from, as of Oct 21, 2008: https://129.128.185.122/drugbank2/drugs/376/fda_labels/730
Crystals from isopropyl alcohol; mp: 264 °C; specific optical rotation: -30 deg at 20 °C/D (c = 0.4% in chloroform). Specific optical rotation: -25 deg at 20 °C/D (c = 0.4% in ethanol). /L-form hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1665
Free base mp 112-113 °C. /L-form/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1665

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Antipsychotics
S57 | GREEKPHARMA | Suspect Pharmaceuticals from the National Organization of Medicine, Greece | DOI:10.5281/zenodo.3248883
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antiparkinson Agents; Muscarinic Antagonists; Parasympatholytics
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

Antiseizure medicines

Medicines for parkinsonism

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

1 of 8
View All
NIST Number
244993
Library
Main library
Total Peaks
109
m/z Top Peak
98
m/z 2nd Highest
218
m/z 3rd Highest
99
Thumbnail
Thumbnail
2 of 8
View All
NIST Number
408520
Library
Replicate library
Total Peaks
131
m/z Top Peak
98
m/z 2nd Highest
55
m/z 3rd Highest
99
Thumbnail
Thumbnail

4.1.2 MS-MS

1 of 6
View All
Spectra ID
Ionization Mode
positive
Top 5 Peaks

302.250946 100

303.252563 60.32

98.097282 58.54

284.237823 8.87

304.254333 8.54

Thumbnail
Thumbnail
Notes
instrument=qTof
2 of 6
View All
Spectra ID
Ionization Mode
Negative
Top 5 Peaks

222.1861 100

77.03955 14.40

137.09744 12.70

300.23519 4.30

Thumbnail
Thumbnail

4.1.3 LC-MS

1 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M-H]-
Precursor m/z
300.2332886
Instrument
Thermo Q Exactive HF
Instrument Type
LC-ESI-QFT
Ionization Mode
negative
Collision Energy
HCD (NCE 20-30-40%)
Top 5 Peaks

222.18636 100

137.09711 63.10

187.11311 3.10

135.08171 1.30

300.23456 1.10

Thumbnail
Thumbnail
2 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+Na]+
Precursor m/z
324.2297826
Instrument
Thermo Q Exactive HF
Instrument Type
LC-ESI-QFT
Ionization Mode
positive
Collision Energy
HCD (NCE 20-30-40%)
Top 5 Peaks

324.22968 100

106.06518 9.20

113.63924 1.20

59.22823 1.10

124.73866 1.10

Thumbnail
Thumbnail

4.2 IR Spectra

IR Spectra
IR: 5196 (Coblentz Society spectral collection)

4.2.1 FTIR Spectra

Technique
KBr WAFER
Source of Sample
Sterling Drug Inc., Sterling-Winthrop Research Institute
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.2.2 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Sigma-Aldrich Company Llc
Catalog Number
Free base of T1516
Lot Number
Free base of 060M1406V
Copyright
Copyright © 2014-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.3 Other Spectra

Intense mass spectral peaks: 98 m/z, 218 m/z, 301 m/z
Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985., p. 527

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Tihexyphenidyl is indicated as an adjunct in the treatment of parkinsonism, an adjuvant in the treatment of parkinsonism with levodopa, and in the control of extrapyramidal disorders caused by central nervous system drugs.

7.2 LiverTox Summary

Trihexyphenidyl is an oral anticholinergic agent used predominantly in the symptomatic therapy of Parkinson disease and movement disorders. Trihexyphenidyl has not been associated with serum enzyme elevations during treatment, but has been implicated in rare cases of acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antiparkinson Agents; Muscarinic Antagonists; Parasympatholytics
Antiparkinson Agents

7.4 WHO Essential Medicines

Drug
Drug Classes
Antiseizure medicines
Formulation
Oral - Solid: 2 mg (hydrochloride); 5 mg (hydrochloride)
Indication
Parkinson disease
Drug
Drug Classes
Medicines for parkinsonism
Formulation
Indication
Parkinson disease

7.5 Clinical Trials

7.5.1 ClinicalTrials.gov

7.6 Therapeutic Uses

Anti-Dyskinesia Agents; Antiparkinson Agents; Muscarinic Antagonists; Parasympatholytics
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Trihexyphenidyl hydrochloride is used for the adjunctive treatment of all forms of parkinsonian syndrome including the postencephalitic, arteriosclerotic, and idiopathic types. Trihexyphenidyl is also used for the relief of parkinsonian signs and symptoms of antipsychotic agent-induced (e.g., butyrophenones, phenothiazines, thioxanthenes) extrapyramidal effects. /Trihexylphenidyl hydrochloride/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663
Clinical results from preliminary trials with trihexyphenidyl in the treatment of other dyskinesias, Huntington's chorea, spasmodic torticollis, and associated disorders have been equivocal.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663
Trihexyphenidyl may also be effective in diminishing the frequency and duration of oculogyric crises, in decreasing salivation, in reducing spastic contractions and involuntary movements characteristic of dyskinesia, and in relieving mental inertia and depression characteristic of all forms of parkinsonian syndrome. As with other antiparkinsonian drugs, tolerance to trihexyphenidyl may develop during prolonged use. The maximum therapeutic response attainable with trihexyphenidyl is in the range of 20-30% symptomatic improvement in 50-75% of patients. Frequently, the maximum response requires empiric combination of trihexyphenidyl with other antimuscarinic drugs or with antihistaminic or dopaminergic agents. Some clinicians believe trihexyphenidyl to be of little value, but the majority have found it a useful adjunct in the multidimensional therapeutic approach to parkinsonian syndrome. Trihexyphenidyl is effective as adjunctive therapy for parkinsonian syndrome in patients receiving levodopa.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663
/EXPL THER/ The influence of two anticholinergic drugs (atropine, trihexyphenidyle) on the effectiveness of antidotal treatment to eliminate soman-induced lethal effects and convulsions was studied in rats. The oxime HI-6 when combined with centrally acting anticholinergic drug trihexyphenidyle seems to be more efficacious in the elimination of acute toxic effects of soman than its combination with atropine. The findings support the hypothesis that the choice of the anticholinergic drug is important for the effectiveness of antidotal mixture in the case of antidotal treatment of soman-induced acute poisoning.
Kassa J, Samnaliev I; Acta Medica (Hradec Kralove) 47 (3): 171-5 (2004)

7.7 Drug Warnings

Adverse reactions to trihexyphenidyl are mainly extensions of its anticholinergic effects. Adverse effects of trihexyphenidyl, which are experienced by 30-50% of patients receiving the drug, may include dryness of the mouth, dizziness, blurred vision, nausea, and nervousness. Other adverse effects typical of those produced by antimuscarinic drugs include constipation, tachycardia, mydriasis, urinary hesitancy or retention, drowsiness, increased intraocular tension, weakness, vomiting, and headache. CNS stimulation, usually manifested by restlessness, agitation, confusion, delirium, and hallucination or euphoria may occur with high dosage, or in persons with a history of hypersensitivity to other drugs, or in patients with arteriosclerosis. Isolated instances of rashes, dilatation of the colon, paralytic ileus, and suppurative parotitis secondary to dryness of the mouth have been reported. Angle-closure glaucoma has reportedly occurred in patients receiving prolonged therapy with trihexyphenidyl. Rarely, psychiatric disturbances such as delusion, amnesia, depersonalization, a sense of unreality, and one possible case of paranoia have been reported with trihexyphenidyl. The incidence and severity of adverse effects are generally dose related and adverse effects may occasionally be obviated by reduction in dosage. If a severe reaction occurs, the drug should be discontinued for several days and then readministered at a lower dosage.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663
Trihexyphenidyl should be used with caution or may be contraindicated in patients with conditions in which anticholinergic effects are undesirable. The usual precautions and contraindications associated with antimuscarinics should be observed with trihexyphenidyl.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663
Tardive dyskinesia may appear in some patients on long-term therapy with antipsychotic drugs or may occur after therapy with these drugs has been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia and, in some instances, may aggravate them. However, parkinsonism and tardive dyskinesia often coexist in patients receiving chronic neuroleptic treatment, and anticholinergic therapy with trihexyphenidyl HCl may relieve some of these parkinsonism symptoms. /Trihexyphenidyl hydrochloride/
US Natl Inst Health; DailyMed. Current Medication Information for Trihexyphenidyl hydrochloride (October 2006). Available from, as of October 7, 2008: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2408
Since the use of trihexyphenidyl hydrochloride may, in some cases, continue indefinitely and since it has atropine-like properties, patients should be subjected to constant and careful long-term observation to avoid allergic and other untoward reactions. Inasmuch as trihexyphenidyl hydrochloride possesses some parasympatholytic activity, it should be used with caution in patients with glaucoma, obstructive disease of the gastrointestinal or genitourinary tracts, and in elderly males with possible prostatic hypertrophy. Geriatric patients, particularly over the age of 60, frequently develop increased sensitivity to the actions of drugs of this type, and hence, require strict dosage regulation. Incipient glaucoma may be precipitated by parasympatholytic drugs such as trihexyphenidyl hydrochloride. /Trihexyphenidyl hydrochloride/
US Natl Inst Health; DailyMed. Current Medication Information for Trihexyphenidyl hydrochloride (October 2006). Available from, as of October 7, 2008: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2408
For more Drug Warnings (Complete) data for TRIHEXYPHENIDYL (10 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Trihexyphenidyl is an antimuscarinic indicated as an adjunct in the treatment of parkinsonism or as a treatment for drug-induced extrapyramidal symptoms. It has a long duration of action as it does not need to be given every day. It has a wide therapeutic window, with acute toxicity being non fatal in doses as high as 300 mg. Patients should have their iridocorneal angle examined before and intraocular pressure monitored during therapy. Patients should be counselled regarding the risk of anhidrosis and hyperthermia.

8.2 MeSH Pharmacological Classification

Antiparkinson Agents
Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists. (See all compounds classified as Antiparkinson Agents.)
Muscarinic Antagonists
Drugs that bind to but do not activate MUSCARINIC RECEPTORS, thereby blocking the actions of endogenous ACETYLCHOLINE or exogenous agonists. Muscarinic antagonists have widespread effects including actions on the iris and ciliary muscle of the eye, the heart and blood vessels, secretions of the respiratory tract, GI system, and salivary glands, GI motility, urinary bladder tone, and the central nervous system. (See all compounds classified as Muscarinic Antagonists.)

8.3 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

N - Nervous system

N04 - Anti-parkinson drugs

N04A - Anticholinergic agents

N04AA - Tertiary amines

N04AA01 - Trihexyphenidyl

8.4 Absorption, Distribution and Excretion

Absorption
Trihexyphenidyl is absorbed from the gastrointestinal tract. Trihexyphenidyl reaches a Cmax of 7.2 ng/mL, with a Tmax of 1.3 hours, and an AUC of 201 ng\*h/mL.
Route of Elimination
Data regarding the route of elimination of trihexyphenidyl are not readily available. However, it is likely eliminated predominantly in the urine.
Using a sensitive radioreceptor assay for anticholinergic drugs, trihexyphenidyl /was assayed/ in human serum and ... its pharmacokinetics following short-term and long-term administration to patients with dystonia /was studied/. Previously untreated patients had a biphasic semilogarithmic plot of serum concentration-time consisting of an initial rapid distribution phase and a later slower elimination phase. Patients on long-term treatment showed only the slower elimination phase. Elimination followed first-order kinetics and was rapid, with a half-life of 3.7 + or - 0.4 (SEM) hours. There was no relationship between half-life and peak serum level, age, duration of therapy, or etiology or severity of dystonia. Although acute anticholinergic side effects paralleled the rise and fall of serum anticholinergic levels, the response of dystonia did not.
Burke RE, Fahn S; Ann Neurol 18 (1): 35-40 (1985)
Trihexyphenidyl is rapidly absorbed from the GI tract. Following oral administration of trihexyphenidyl hydrochloride tablets, the onset of action occurs within 1 hour, peak effects last 2-3 hours, and the duration of action is 6-12 hours. The metabolic fate of trihexyphenidyl has not been determined; the drug is excreted in the urine, probably as unchanged drug. /Trihexylphenidyl hydrochloride/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663
The subcellular distribution of biperiden (BP), trihexyphenidyl (TP) and (-)-quinuclidinyl benzylate (QNB) in brain, heart and lung following high dose (3.2 mg/kg) iv administration was investigated in rats. The subcellular distribution of BP or TP used clinically conformed with that of QNB, a typical potent central muscarinic antagonist. The concentration-time courses of the brain subcellular fractions for these drugs were of two types which decreased slowly and in parallel to the plasma concentration. The subcellular distribution in the brain and heart was dependent on the protein amount of each fraction. The percent post-nuclear fraction (P2) of the total concentration in the lung was characteristically about 3-5 times larger than that in the heart. It was elucidated that the distribution in the lung differs from that in the brain and heart, with high affinity which is not dependent on the protein amount in the P2 fraction containing lysosomes. On the other hand, at a low dose (650 ng/kg) of 3H-QNB, each fraction as a percentage of the total concentration in the brain increased in synaptic membrane and synaptic vesicles and decreased in nuclei and cytosol as compared with the high dose. These results show that although the tissue concentration-time courses of anticholinergic drugs appear to decrease simply in parallel to plasma concentration, the subcellular distribution exhibits a variety of patterns among various tissues.
Ishizaki J et al; Biol Pharm Bull 21 (1): 67-71(1998)
Twenty-four male subjects were randomized to receive two oral dosage forms of trihexyphenidyl HCl (alpha-cyclohexyl-alpha-phenyl-1-piperidinepropanol HCl). The dosage regimens were (1) a 5-mg immediate release (IR) tablet given twice daily at time zero and 12 hr later, and (2) two 5-mg sustained-release (SR) capsule formulations given daily. The number of adverse experiences following the SR formulation were approximately 50% of those for the IR formulation, the peak concentration (Cmax) after the SR formulation was significantly lower (p less than 0.05) than that after the first dose of the IR formulation, and the time to reach Cmax (tmax) was significantly longer after the SR formulation (p less than 0.05). The SR formulation maintained serum concentrations above 50, 60, and 70% of Cmax values for average time periods of 11.7, 9.4, and 5.9 hr, respectively, compared with values of 1.8, 1.2, and 0.9 hr after the IR formulation; the differences were all significant (p less than 0.05). The mean elimination half-life (t1/2) was similar (p greater than 0.05) after the SR (10.1 hr) and IR (8.7 hr) formulations. The statistical power of the study was 98.1% to detect a 20% difference in the area under the curve from time zero to time infinity (AUC0----infinity) between formulations. Although the AUC0----infinity after the SR formulation was statistically smaller (p less than 0.05) than after the IR tablet, the difference was less than 20%. Therefore, the SR formulation was bioequivalent to the IR tablet formulation of trihexyphenidyl. /Trihexylphenidyl hydrochloride/
Cheung WK et al; J Pharm Sci 77 (9): 748-50 (1988)

8.5 Metabolism / Metabolites

Data regarding the metabolism of trihexyphenidyl are not readily available. However, it is likely not heavily metabolized.
Benzhexol and three of its metabolites excreted in urine in man have been investigated by glc.--mass spectrometry. Three isomeric hydroxylated metabolites were identified as the 1-(hydroxycyclohexyl)-1-phenyl-3-piperidinopropan-1-ols. 3. The amounts of benzhexol and its identified metabolites have been semiquantitatively determined after a single oral dose in two healthy adults. Approx. 56% of the dose was excreted as the hydroxylated metabolites. The levels of benzhexol excreted were too low to be measured by the techniques used.
Nation RL et al; Xenobiotica 8 (3): 165-9 (1978)
Half Life: 3.3-4.1 hours

8.6 Biological Half-Life

The mean elimination half life of trihexyphenidyl is 3.2 ± 0.3 hours.
Twenty-four male subjects were randomized to receive two oral dosage forms of trihexyphenidyl HCl (alpha-cyclohexyl-alpha-phenyl-1-piperidinepropanol HCl). The dosage regimens were (1) a 5-mg immediate release (IR) tablet given twice daily at time zero and 12 hr later, and (2) two 5-mg sustained-release (SR) capsule formulations given daily. ... The mean elimination half-life (t1/2) was similar (p greater than 0.05) after the SR (10.1 hr) and IR (8.7 hr) formulations. /Trihexylphenidyl hydrochloride/
Cheung WK et al; J Pharm Sci 77 (9): 748-50 (1988) T
Using a sensitive radioreceptor assay for anticholinergic drugs, trihexyphenidyl /was assayed/ in human serum and ... its pharmacokinetics following short-term and long-term administration to patients with dystonia /was studied/. ... Elimination followed first-order kinetics and was rapid, with a half-life of 3.7 + or - 0.4 (SEM) hours. There was no relationship between half-life and peak serum level, age, duration of therapy, or etiology or severity of dystonia. ...
Burke RE, Fahn S; Ann Neurol 18 (1): 35-40 (1985)

8.7 Mechanism of Action

Trihexyphenidyl is a non-selective muscarinic acetylcholine receptor antagonist but binds with higher affinity to the M1 subtype. In vivo studies have shown that trihexyphenidyl demonstrates higher affinity for central muscarinic receptors located in the cerebral cortex and lower affinity for those located peripherally. Other studies suggest that trihexyphenidyl may modify nicotinic acetylcholine receptor neurotransmission, leading indirectly to enhanced dopamine release in the striatum. Although the anticholinergic has proven to be useful in the treatment of symptoms associated with Parkinson’s disease or other movement disorders, its mechanism of action has yet to be fully elucidated.
Cerebral blood flow and oxygen metabolism were studied in six previously untreated patients with Parkinson's disease (PD) before and after anticholinergic treatment using positron emission tomography (PET) and compared with six controls. The PET study and an assessment of the disability and cognitive impairment were performed before and after administration of 6 mg trihexyphenidyl for 5 to 11 weeks. All PD patients showed improvements in motor symptoms after the trihexyphenidyl treatment. Cognitive function did not significantly differ between before and after trihexyphenidyl treatment. However, after trihexyphenidyl treatment, regional cerebral blood flow (rCBF) and regional oxygen metabolic rate (rCMRO2) decreased by 15% in the striatum and by 10% in all cortical areas contralateral to predominantly symptomatic limbs, and by 10% in the ipsilateral striatum and all cortical areas, significantly below the values of controls in most cerebral cortices and striatum. These findings suggest that trihexyphenidyl inhibits the cortical cholinergic system and significantly decreases rCBF and rCMRO2 in the cerebral cortices without cognitive impairment in untreated patients with PD.
Takahashi S et al; J Neurol Sci 167 (1): 56-61 (1999)
In common with other antimuscarinic agents, trihexyphenidyl produces an atropine-like blocking action on parasympathetic-innervated peripheral structures, including smooth muscle. In addition, trihexyphenidyl exhibits a direct spasmolytic action on smooth muscle and exhibits weak mydriatic, antisialagogue, and cardiovagal blocking effects. The exact mechanism of action of trihexyphenidyl in parkinsonian syndrome is not understood but may result from blockade of efferent impulses and from central inhibition of cerebral motor centers. In small doses, trihexyphenidyl depresses the CNS but larger doses cause cerebral excitement resembling the signs of atropine toxicity.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663
In vivo microdialysis was used to study the effect of the non-selective muscarinic antagonist, trihexyphenidyl, on the decarboxylation of levodopa (L-dopa) in the striatum of hemi-Parkinson rats. In normal rats, continuous perfusion of trihexyphenidyl (1 mM) via the microdialysis probe induced a significant increase in striatal dopamine release, followed by a decrease to below baseline values. A similar effect was observed, though less pronounced, in denervated striatum of rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. In these hemi-Parkinson rats, continuous striatal perfusion of trihexyphenidyl had no effect on the biotransformation of locally applied L-dopa (2 uM for 20 min) to dopamine in either intact or denervated striatum. However, systemic administration of trihexyphenidyl (1.5 mg/kg ip) produced an attenuation of the L- dopa-induced dopamine release in the intact striatum (contralateral to the lesion) of hemi-Parkinson rats. This effect was absent in the denervated striatum of these animals. We confirmed that L-dopa induces an increase in striatal dopamine output which is influenced by the severity of the dopaminergic denervation. The absence of an effect of trihexyphenidyl locally applied in the striatum, on biotransformation of L-dopa suggests that the site of action of antimuscarinic drugs may not be in the striatum and, therefore, remains unclear.
Izurieta-Sanchez P et al; Eur J Pharmacol 353 (1): 33-42 (1998)

8.8 Human Metabolite Information

8.8.1 Cellular Locations

Membrane

9 Use and Manufacturing

9.1 Uses

Synthetic antispasmodic ... adjunct in the treatment of all forms of parksinonism (postencephalitic, arteriosclerotic, and idiopathic) /Trihexylphenidyl hydrochloride/
FDA; MedWatch. Artane. W10450C001. ET01. Rev 03/03. Washington, DC: Food Drug Admin. Available from, as of Oct 21, 2008: https://www.fda.gov/medwatch/SAFETY/2003/03Jun_PI/Artane_PI.pdf
THERAP CAT: Antiparkinsonian /Trihexylphenidyl hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1665
MEDICATION

Use (kg; approx.) in Germany (2009): >10

Use (kg) in France (2004): 257

Consumption (g per capita; approx.) in Germany (2009): 0.000122

Consumption (g per capita) in France (2004): 0.00425

Calculated removal (%): 72.7

Indicated for the treatment of parkinson's disease and extrapyramidal reactions caused by drugs.

9.1.1 Use Classification

Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

ACETOPHENONE & PIPERIDINE ARE CAUSED TO UNDERGO MANNICH CONDENSATION WITH FORMALDEHYDE... 3-PIPERIDINOPROPIOPHENONE THUS PRODUCED IS ISOLATED & SUBJECTED TO TYPICAL GRIGNARD REACTION WITH CYCLOHEXYLMAGNESIUM CHLORIDE TO YIELD...TRIHEXYPHENIDYL BASE. HYDROCHLORIDE IS...PREPD BY...PPTN WITH...HYDROGEN CHLORIDE. /HCL/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 859
Adamson, Wilkinson, US 2682543 (1954 to Burroughs Wellcome); Denton, US 2716121 (1955 to American Cyanamide). /Trihexyphenidyl hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1665

9.3 Impurities

1-phenyl-3-(piperidine-1-yl)propan-1-one
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th Ed., Volume 2; Strasbourg, France, p.2625 (2004)

9.4 Formulations / Preparations

Trade Names. Artane (Lederle), Bentex (Steinhard), Broflex (Bio-Med), Pargitan (KabiVitrum), Parkinane (Lederle), Triphenidone (Toho). /Trihexylphenidyl hydrochloride/
Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V25 167 (2003)
Oral: Elixir: 2 mg/5 mL Trihexyphenidyl Hydrochloride Elixir (Mikart), (Pharmaceutical Associates), (Pharmaceutical Ventures). Tablets: 2 mg Trihexyphenidyl Hydrochloride Tablets (URL), (Vintage), (Watson), (West-Ward); 5 mg Trihexyphenidyl Hydrochloride Tablets (URL), (Vintage), (Watson), (West-Ward). /Trihexypheridyl hydrochloride/
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663

9.5 General Manufacturing Information

TRIHEXYPHENIDYL MAY BE COMBINED WITH OTHER ANTIPARKINSONIAN DRUGS.
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 860

10 Identification

10.1 Analytic Laboratory Methods

CHROMATOGRAPHIC DATA FOR METHADONE & RELATED DRUGS; GLC RETENTION TIMES RELATIVE TO TRIHEXYLPHENIDYL & RF VALUES IN TLC SYSTEM FOR COMMON BASIC DRUGS LIKELY TO BE PRESENT IN POISONING INCIDENTS. /FROM TABLE/
Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975., p. 235
FLUORIMETRIC PROCEDURE IS DESCRIBED FOR DETECTION OF ARTANE (TRIHEXYLPHENIDYL HYDROCHLORIDE) IN TABLET FORMULATIONS. /Trihexylphenidyl hydrochloride/
GELBOKE M; FLUORIMETRIC DETERMINATION OF TRIHEXYPHENIDYL HYDROCHLORIDE & SOME STRUCTURAL ANALOG DERIVATIVES; J PHARM BELG 31 (4) 367-402 (1976)
Analyte: trihexyphenidyl hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /trihexyphenidyl hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.3462 (2008)
Analyte: trihexyphenidyl hydrochloride; matrix: chemical identification; procedure: retention time of the major peak of the liquid chromatogram with comparison to standards /trihexyphenidyl hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.3462 (2008)
For more Analytic Laboratory Methods (Complete) data for TRIHEXYPHENIDYL (12 total), please visit the HSDB record page.

10.2 Clinical Laboratory Methods

Analyte: trihexyphenidyl; matrix: blood (plasma, whole); procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm; limit of detection: 10 ng/mL
Curry SH et al; J Chromatogr 231: 361-376 (1982). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: trihexyphenidyl; matrix: blood (plasma); procedure: high-performance liquid chromatography with electrochemical detection
Le Moing JP et al; J Chromatogr 614: 333-339 (1993). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: trihexyphenidyl; matrix: blood (serum, whole), tissue (liver); procedure: high-performance liquid chromatography with ultraviolet detection at 220 nm
McIntyre IM et al; J Chromatogr 621: 215-223 (1993). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: trihexyphenidyl; matrix: blood (whole), urine; procedure: high-performance liquid chromatography with ultraviolet detection at 200.5 nm
Gaillard Y, Pepin G; J Chromatogr A 763: 149-163 (1997). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Acute Toxic
Signal
Danger
GHS Hazard Statements
H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P316, P321, P330, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 2 reports by companies from 1 notifications to the ECHA C&L Inventory.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 3 (100%)

11.2 Accidental Release Measures

11.2.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.3 Handling and Storage

11.3.1 Storage Conditions

Trihexyphenidyl hydrochloride tablets should be stored in tight containers at 15-30 °C. Trihexyphenidyl hydrochloride elixir should be stored at controlled room temperature (20-25 °C); freezing of the elixir should be avoided.
American Society of Health System Pharmacists. AHFS Drug Information 2008. Bethesda, Maryland 2008, p. 2663

11.4 Regulatory Information

REACH Registered Substance
New Zealand EPA Inventory of Chemical Status
1-Piperidinepropanol, .alpha.-cyclohexyl-.alpha.-phenyl-: Does not have an individual approval but may be used under an appropriate group standard

11.4.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl trihexyphenidyl hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Trihexyphenidyl hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of October 29, 2008: https://www.fda.gov/cder/ob/

11.5 Other Safety Information

Chemical Assessment

IMAP assessments - 1-Piperidinepropanol, .alpha.-cyclohexyl-.alpha.-phenyl-: Human health tier I assessment

IMAP assessments - 1-Piperidinepropanol, .alpha.-cyclohexyl-.alpha.-phenyl-: Environment tier I assessment

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

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.

12.1.2 Hepatotoxicity

Trihexyphenidyl has not been reported to cause serum aminotransferase elevations, but it has not been evaluated for effects on serum enzyme levels in a prospective manner. Trihexyphenidyl was cited as the cause of two cases of acute liver injury resulting in death in the Japanese literature, but few details were given and there have been no other reports of such injury in the literature in the subsequent 40 years. Thus, trihexyphenidyl must be a very rare cause of liver injury, if it occurs at all.

Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

12.1.3 Drug Induced Liver Injury

Compound
trihexyphenidyl
DILI Annotation
No-DILI-Concern
Label Section
No match
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.5 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited information indicates that maternal doses of trihexyphenidyl up to 4 mg daily together with haloperidol or risperidone did not produce any adverse effects in breastfed infants. Long-term use of trihexyphenidyl might reduce milk production or milk letdown, but a single dose is not likely to interfere with breastfeeding. The prolactin elevating effect of concurrent antipsychotic agents might counteract any prolactin lowering effect of trihexyphenidyl. During long-term use, observe for signs of decreased lactation (e.g., infant insatiety and poor weight gain).

◉ Effects in Breastfed Infants

One woman with schizophrenia took trihexyphenidyl and haloperidol during 3 pregnancies and postpartum. The trihexyphenidyl dose was 4 mg daily in all 3 pregnancies. She breastfed (extent not stated) all 3 children for 6 to 8 months using the same doses. Development was age-appropriate in all children aged 16 months at 8 years of age at the time of assessment.

A woman diagnosed with undifferentiated schizophrenia took risperidone 4 to 5 mg and trihexyphenidyl 2 mg daily throughout 5 pregnancies. She breastfed each infant for 20 to 24 months. No adverse developmental consequences were noted in any of the children. At the time of publication, the oldest three children, aged 26, 23 and 22 years, had completed their education and were employed, while the youngest two were 15 and 19 years old and were doing well academically in their education.

◉ Effects on Lactation and Breastmilk

Anticholinergics can inhibit lactation in animals, apparently by inhibiting growth hormone and oxytocin secretion. Anticholinergic drugs can also reduce serum prolactin in nonnursing women. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

One woman with schizophrenia took trihexyphenidyl and haloperidol during 3 pregnancies and postpartum. She was able to breastfeed (extent not stated) all 3 children for 6 to 8 months.

A woman diagnosed with undifferentiated schizophrenia took risperidone 4 to 5 mg and trihexyphenidyl 2 mg daily throughout 5 pregnancies. She successfully breastfed each infant for 20 to 24 months.

12.1.6 Exposure Routes

Oral. Trihexyphenidyl is rapidly absorbed from the gastrointestinal tract.

12.1.7 Symptoms

Symptoms of overdose include mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Central consequences are agitation, confusion, and hallucinations.

12.1.8 Acute Effects

12.1.9 Treatment

Treatment of acute overdose involves symptomatic and supportive therapy. Gastric lavage or other methods to limit absorption should be instituted. A small dose of diazepam or a short-acting barbiturate may be administered if CNS excitation is observed. Phenothiazines are contraindicated because the toxicity may be intensified due to their antimuscarinic action, causing coma. Respiratory support, artificial respiration or vasopressor agents may be necessary. Hyperpyrexia must be reversed, fluid volume replaced and acid-balance maintained. Urinary catheterization may be necessary. It is not known if Trihexyphenidyl is dialyzable. (L1712)
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

12.1.10 Interactions

When trihexyphenidyl hydrochloride is used concomitantly with levodopa, the usual dose of each may need to be reduced. Careful adjustment is necessary, depending on side effects and degree of symptoms control. /Trihexylphenidyl hydrochloride/
Novak, K.M. (ed.). Drug Facts and Comparisons2008 Edition. Wolters Kluwer Health. St. Louis, Missouri 2008., p. 1614
...CENTRALLY ACTING ANTICHOLINERGIC AGENTS THAT MAY EXACERBATE TARDIVE DYSKINESIA /CAUSED BY CHLORPROMAZINE/ INCL...TRIHEXYPHENIDYL.
Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978., p. 20
Trihexyphenidyl, applied in doses of 30 and 50 mg/kg (ip), did not influence the electroconvulsive threshold per se but when combined with valproate, strongly enhanced its anticonvulsant activity against maximal electroshock-induced seizures /in mice/ lowering the ED50 from 206 to 103 and 46 mg/kg, respectively. The chimney test and retention testing in mice revealed that administration of ... trihexyphenidyl at 30 mg/kg (ip) together with valproate in doses of 130 or 103 mg/kg (ip), respectively, resulted in motor impairment and caused impairment of long-term memory, similar to the effects of valproate alone, when applied at its ED50 against maximal electroshock. ... trihexyphenidyl /did not/ alter the total level of valproate in plasma. ...
Urbanska E et al; Neuropharmacology 31 (10): 1021-6 (1992)

12.1.11 Antidote and Emergency Treatment

Emergency and supportive measures: Maintain an open airway and assist ventilation if needed. Treat hyperthermia, coma, rhabdomyolysis, and seizures if they occur. /Anticholinergics/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 87
Specific drugs and antidotes: A small dose of physostigmine .... can be given to patients with severe toxicity (e.g., hyperthermia, severe delirium, or tachycardia). Caution: Physostigmine can cause AV block, asystole, and seizures, especially in patients with tricyclic antidepressant overdose. Neostigmine, a peripherally acting cholinesterase inhibitor, may be useful in treating anticholinergic-induced ileus. /Anticholinergics/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 87
Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of slowed gastrointestinal motility, gut decontamination procedures may be helpful even in late-presenting patients. /Anticholinergics/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 87
Enhanced elimination: Hemodialysis, hemoperfusion, peritoneal dialysis, and repeat-dose charcoal are not effective in removing anticholinergic agents. /Anticholinergics/
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 87
For more Antidote and Emergency Treatment (Complete) data for TRIHEXYPHENIDYL (7 total), please visit the HSDB record page.

12.1.12 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ ... In a group of 22 psychiatric patients receiving long-term antipsychotic medication concurrently with trihexyphenidyl the effects of trihexyphenidyl withdrawal were studied double-blind and placebo controlled. Anxiety, psychotic symptoms, extrapyramidal symptoms and salivary flow were monitored. Blood pressure, pulse, sleep duration, weight and body temperature were recorded daily. The result was a recognizable withdrawal syndrome indicated by an increase in anxiety with various physical complaints, as well as evidence of orthostatic hypotension and tachycardia. A temporary deterioration was noted in psychotic symptomatology and extrapyramidal symptoms. The majority of the parameters regained baseline values, indicating the symptoms were related to the discontinuation of trihexyphenidyl and supporting the existence of a withdrawal syndrome.
McInnis M, Petursson H; Acta Psychiatr Scand 71 (3): 297-303 (1985)
/SIGNS AND SYMPTOMS/ In Brazil, the medicinal misuse of trihexyphenidyl has been observed among several segments of society. The present study was conducted in the city of Sao Paulo during 2002 to characterize this abuse. A sample of 21 users and 16 ex-users was interviewed using qualitative methodology; the subjects were single, unemployed, male polydrug users, who used trihexyphenidyl in order to attain states of mental alterations, mainly hallucinations and deliriums. Trihexyphenidyl is consumed in association with alcohol, other licit drugs (benzodiazepines), or illicit drugs, impairing cognitive functions such as memory, attention, and learning, intervening with some activities of users' daily life.
Nappo SA et al; Subst Use Misuse 40 (4): 473-82 (2005)
/CASE REPORTS/ ... Two case reports of trihexyphenidyl abuse /are described/. In one of the cases a double-blind, placebo-controlled withdrawal was conducted and monitored on a number of physiological parameters and the Hamilton Anxiety Rating Scale. A recognizable withdrawal syndrome followed discontinuation of the drug. ...
McInnis M, Petursson H; Acta Psychiatr Scand 69 (6): 538-42 (1984)
/CASE REPORTS/ ... The case presented is of anti-cholinergic abuse by a chronic schizophrenic who abused trihexyphenidyl, up to 200 mg per day, to achieve an euphoric effect. The drug was partly prescribed in psychiatric clinics, but mostly bought in the drugstore. The discontinuance of trihexyphenidyl produced anxiety, which was relieved by anxiolytics. The patient also feigned extrapyramidal symptoms to get anticholinergic injections during drug abstinence. ...
Lo Y, Tsai SJ; Zhonghua Yi Xue Za Zhi (Taipei) 57 (2): 157-60 (1996)
For more Human Toxicity Excerpts (Complete) data for TRIHEXYPHENIDYL (13 total), please visit the HSDB record page.

12.1.13 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Neurotoxicity/ An amnesic effect ... induced by trihexyphenidyl and biperiden, clinically used in the parkinsonism and schizophrenic patients, /was studied/ by using passive avoidance tasks. Both of these drugs (0.1-10 mg/kg, sc) showed dose-dependent amnesic effects in the acquisition and retrieval phases. However, the effect induced by trihexyphenidyl was transient, whereas that of biperiden was long-lasting. To clarify the reason for the different duration of the amnesic activity, binding to the muscarinic receptor was examined. In the Scatchard analysis, trihexyphenidyl competed with [(3)H]quinuclidinyl benzilate ([(3)H]QNB) on the muscarinic receptor (showed increased K(d) and unchanged B(max) value), while biperiden decreased [(3)H]QNB binding (B(max) value) significantly. Furthermore, in an exchange assay for receptor inactivation, trihexyphenidyl binding to muscarinic receptors was exchanged by [(3)H]QNB completely, but biperiden decreased the exchangeable binding of [(3)H]QNB in a dose dependent manner (0.1-100 nM). ...
Kimura Y et al; Brain Res 834 (1-2): 6-12 (1999)
/LABORATORY ANIMALS: Neurotoxicity/ The purpose of the present study was to make a comparative assessment of potential cognitive effects of benactyzine (0.3 mg/kg), biperiden (0.11 mg/kg), caramiphen (10 mg/kg), procyclidine (3 mg/kg), and trihexyphenidyl (0.12 mg/kg) separately and each in combination with physostigmine (0.1 mg/kg). The results showed that benactyzine, caramiphen, and trihexyphenidyl reduced rats' innate preference for novelty, whereas biperiden and procyclidine did not. When benactyzine, caramiphen, and trihexyphenidyl were combined with physostigmine the cognitive impairment disappeared. This counteracting effect, however, caused changes in locomotor and rearing activities not seen by each drug alone. Acetylcholinesterase inhibitors and anticholinergics used as prophylactics can offset each other, but exceptions are observed in a previous study when a very potent anticholinergic (scopolamine) or a high dose of procyclidine still results in cognitive deficits in spite of coadministration with physostigmine.
Myhrer T et al; Pharmacol Biochem Behav 89 (4): 633-8 (2008)

12.1.14 Populations at Special Risk

The /apolipoprotein E/ epsilon4 allele in healthy elderly was associated with increased subjective mental slowing after trihexyphenidyl anticholinergic challenge.
Pomara N et al; Am J Geriatr Psychiatry 16 (2): 116-24 (2008)

12.1.15 Protein Binding

Data regarding the extent of trihexyphenidyl protein binding in plasma are not readily available. Trihexyphenidyl is 36.13-41.92% bound to albumin under controlled conditions in a dialysis bag.

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Chemical Co-Occurrences in Literature

14.6 Chemical-Gene Co-Occurrences in Literature

14.7 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Drug-Food Interactions

Take with or without food. Taking with food may minimize stomach upset. May take before meals to mitigate dry mouth or may take after meals to reduce excess salivation.

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 KEGG: Target-based Classification of Drugs

18.6 KEGG: Drug Groups

18.7 WHO ATC Classification System

18.8 ChemIDplus

18.9 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.10 ChEMBL Target Tree

18.11 UN GHS Classification

18.12 NORMAN Suspect List Exchange Classification

18.13 CCSBase Classification

18.14 EPA DSSTox Classification

18.15 EPA Substance Registry Services Tree

18.16 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    1-Piperidinepropanol, .alpha.-cyclohexyl-.alpha.-phenyl-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  5. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  6. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  7. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  8. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  9. Hazardous Substances Data Bank (HSDB)
  10. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  11. New Zealand Environmental Protection Authority (EPA)
    LICENSE
    This work is licensed under the Creative Commons Attribution-ShareAlike 4.0 International licence.
    https://www.epa.govt.nz/about-this-site/general-copyright-statement/
  12. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  13. ChEBI
  14. LiverTox
  15. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  16. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  17. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  18. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  19. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  20. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  21. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  22. Therapeutic Target Database (TTD)
  23. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  24. Drugs and Lactation Database (LactMed)
  25. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    TRIHEXYPHENIDYL
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  26. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  27. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  28. Japan Chemical Substance Dictionary (Nikkaji)
  29. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  30. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  31. Metabolomics Workbench
  32. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  33. SpectraBase
  34. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  35. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  36. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  37. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  38. Springer Nature
  39. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  40. Wikidata
  41. Wikipedia
  42. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  43. PubChem
  44. GHS Classification (UNECE)
  45. EPA Substance Registry Services
  46. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  47. PATENTSCOPE (WIPO)
  48. NCBI
CONTENTS