View source for Trihexyphenidyl

{{Short description|Antispasmodic drug}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields      = changed
| verifiedrevid      = 470614772
| IUPAC_name         = (''RS'')-1-Cyclohexyl-1-phenyl-3-(1-piperidyl)propan-1-ol
| image              = Trihexyphenidyl.svg
| image_class = skin-invert-image
| image2             = Trihexyphenidyl 3D.png
| tradename          = Artane, Parkin,{{fact|date=April 2025}} Pacitane, Hexymer
| Drugs.com          = {{drugs.com|monograph|trihexyphenidyl-hydrochloride}}
| MedlinePlus        = a682160
| DailyMedID         = Trihexyphenidyl
| pregnancy_AU       = B1
| legal_BR           = B1
| legal_BR_comment   = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_US           = Rx-Only
| routes_of_administration = Oral, as tablet or [[elixir]]
<!--Pharmacokinetic data-->| bioavailability    =
| protein_bound      =
| metabolism         =
| elimination_half-life = 3.3-4.1 hours
<!--Identifiers-->| IUPHAR_ligand      = 7315
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 144-11-6
| ATC_prefix         = N04
| ATC_suffix         = AA01
| ATC_supplemental   =
| PubChem            = 5572
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00376
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 5371
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 6RC5V8B7PO
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D08638
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 1490
<!--Chemical data-->| C                  = 20
| H                  = 31
| N                  = 1
| O                  = 1
| smiles             = OC(c1ccccc1)(CCN2CCCCC2)C3CCCCC3
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 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
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = HWHLPVGTWGOCJO-UHFFFAOYSA-N
}}

'''Trihexyphenidyl''' ('''THP''',  '''benzhexol''', '''trihex''', marketed as '''Artane''' and others) is an [[antispasmodic]] drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the [[antimuscarinic]] class and is often used  in [[Management of Parkinson's disease#Medication|management of Parkinson's disease]]. It was approved by the [[Food and Drug Administration|FDA]] for the treatment of Parkinson's in the US in 2003.<ref>{{Cite web|title=TGA eBS - Product and Consumer Medicine Information Licence|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2016-PI-01605-1&d=202008201016933|access-date=2020-08-20|website=www.ebs.tga.gov.au}}</ref><ref>{{Cite web| work = U.S. Food and Drug Administration |date=2003-05-25|title=New Drug Application Approval Notice|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/006773_S036_ARTANE.pdf|access-date=2020-08-20}}</ref>

It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

== Medical uses ==
Trihexyphenidyl is used for the symptomatic treatment of [[Parkinson's disease]] in mono and combination therapy.<ref>{{cite journal | vauthors = Harris MK, Shneyder N, Borazanci A, Korniychuk E, Kelley RE, Minagar A | title = Movement disorders | journal = The Medical Clinics of North America | volume = 93 | issue = 2 | pages = 371–88, viii | date = March 2009 | pmid = 19272514 | doi = 10.1016/j.mcna.2008.09.002 | series = Common Neurologic Disorders }}</ref> It is active in [[Postencephalitic parkinsonism|postencephalitic]], [[arteriosclerotic]], and [[idiopathic]] forms. The drug is also commonly used to treat [[Extrapyramidal symptoms|extrapyramidal]] side effects occurring during [[antipsychotic]] treatment. It reduces the frequency and duration of [[oculogyric crisis|oculogyric crises]] as well as of [[Dyskinesia|dyskinetic]] movements and spastic contractions.  Trihexyphenidyl may improve [[psychotic depression]] and mental inertia frequently associated with Parkinson's disease and symptomatic problems caused by antipsychotic treatment.{{medical citation needed|date=May 2017}} The drug cannot cure Parkinson's disease, but may provide substantial alleviation of symptoms. An estimated 50–75% of people with Parkinson's disease will react positively and experience a 20–30% symptomatic improvement. To increase therapeutic activity, trihexyphenidyl is often given concomitantly with [[levodopa]] or other [[antimuscarinic]] or [[antihistaminic]] (e.g. [[diphenhydramine]]) agents. [[Combination therapy]] with [[dopamine agonist]]s such as [[cabergoline]] is also possible. This is often termed a 'multidimensional approach'.{{medical citation needed|date=May 2017}}

Trihexyphenidyl has also been prescribed for [[essential tremor]] and [[akathisia]].<ref>{{cite journal | vauthors = Inada T | title = [Drug-Induced Akathisia] | journal = Brain and Nerve = Shinkei Kenkyu No Shinpo | volume = 69 | issue = 12 | pages = 1417–1424 | date = December 2017 | pmid = 29282345 | doi = 10.11477/mf.1416200927 }}</ref><ref>{{cite journal | vauthors = Duma SR, Fung VS | title = Drug-induced movement disorders | journal = Australian Prescriber | volume = 42 | issue = 2 | pages = 56–61 | date = April 2019 | pmid = 31048939 | pmc = 6478951 | doi = 10.18773/austprescr.2019.014 }}</ref>

In pediatrics, it has been used for children with [[dystonia]] due to [[cerebral palsy]],<ref>{{cite journal | vauthors = Ben-Pazi H | title = Trihexyphenidyl improves motor function in children with dystonic cerebral palsy: a retrospective analysis | journal = Journal of Child Neurology | volume = 26 | issue = 7 | pages = 810–816 | date = July 2011 | pmid = 21498790 | doi = 10.1177/0883073810392582 }}</ref><ref>{{cite journal | vauthors = Sanger TD, Bastian A, Brunstrom J, Damiano D, Delgado M, Dure L, Gaebler-Spira D, Hoon A, Mink JW, Sherman-Levine S, Welty LJ | title = Prospective open-label clinical trial of trihexyphenidyl in children with secondary dystonia due to cerebral palsy | journal = Journal of Child Neurology | volume = 22 | issue = 5 | pages = 530–7 | date = May 2007 | pmid = 17690057 | doi = 10.1177/0883073807302601 | s2cid = 73087776 }}</ref><ref>{{cite book | vauthors = Tarnopolsky M, Alshahoumi R | chapter = "Complex I Deficiency | veditors = Saneto R, Parikh S, Cohen BH | title = Mitochondrial Case Studies: Underlying Mechanisms and Diagnosis. | publisher = Academic Press | date = November 2015 | pages = 257–64 | isbn = 978-0-12-801149-2 }}</ref> and to control [[drooling]].<ref>{{cite journal | vauthors = Reid SM, Westbury C, Guzys AT, Reddihough DS | title = Anticholinergic medications for reducing drooling in children with developmental disability | journal = Developmental Medicine and Child Neurology | volume = 62 | issue = 3 | pages = 346–353 | date = March 2020 | pmid = 31495925 | doi = 10.1111/dmcn.14350 | hdl = 11343/286392 | hdl-access = free }}</ref>

In [[organophosphate poisoning]], trihexyphenidyl is a more effective [[antidote]] than atropine to counteract the cholinergic crisis, seizures, and neuropathology.<ref>{{cite journal | vauthors = Aracava Y, Albuquerque EX, Pereira EF | title = (R,S)-trihexyphenidyl, acting via a muscarinic receptor-independent mechanism, inhibits hippocampal glutamatergic and GABAergic synaptic transmissions: Potential relevance for treatment of organophosphorus intoxication | journal = Neuropharmacology | volume = 239 | pages = 109684 | date = November 2023 | pmid = 37549771 | pmc = 10590273 | doi = 10.1016/j.neuropharm.2023.109684 }}</ref>

Equivocal preliminary results from small studies exist for other dyskinesias, [[Huntington's chorea]], Spasmodic [[torticollis]].{{medical citation needed|date=May 2017}}

== Contraindications ==
Contraindications include according to the Therapeutic Goods Administration Australia from 2022:<ref>{{Cite web | work = Therapeutic Goods Administration  |date=July 2022 |title=TGA eBS - Product and Consumer Medicine Information Licence |url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2016-PI-01605-1&d=202008201016933 |access-date=2024-02-12 | publisher = Australian Government }}</ref>
* Hypersensitivity to trihexyphenidyl
* Narrow angle [[glaucoma]]
* [[Ileus]] (disruption of the normal propulsive ability of the intestine)
* Caution: People with obstructive diseases of the urogenital tract, people with a known history of seizures and those with potentially dangerous [[tachycardia]]
* People under 18 years of age should not be treated due to a lack of clinical experience.
* People should allow a period to adjust to the dose when first starting trihexyphenidyl and when the dose has been increased or added to a regimen with other drugs because acute somnolence and accumulated fatigue can make it particularly dangerous to operate an automobile, heavy machinery etc.

== Adverse effects ==
Dose-dependent [[adverse drug reaction|side effect]]s are frequent, but typically lessen over time as the body adapts to the medication. All of the following symptoms considered, Artane has been shown to dramatically and consistently improve neurologic defects in people aged 16–86 over the course of five years.<ref name="pmid13151847">{{cite journal | vauthors = Doshay LJ, Constable K, Zier A | title = Five year follow-up of treatment with trihexyphenidyl (artane); outcome in four hundred eleven cases of paralysis agitans | journal = Journal of the American Medical Association | volume = 154 | issue = 16 | pages = 1334–6 | date = April 1954 | pmid = 13151847 | doi = 10.1001/jama.1954.02940500014005 }}</ref> People who are older or who have psychiatric conditions may become confused or develop [[delirium]]. Side effects include but are not limited to:<ref>{{Cite web |date=nd |title=Trihexyphenidyl |url=http://www.webmd.com/drugs/2/drug-8720/trihexyphenidyl-oral/details#side-effects |website=Web MD |publisher=First Databank Inc}}</ref>
* Central nervous system: [[drowsiness]], [[Vertigo (medical)|vertigo]], [[headache]], and [[dizziness]] are frequent. With high doses nervousness, agitation, [[anxiety]], delirium, and confusion are noted. Trihexyphenidyl may be abused due to a short acting mood-elevating and euphoric effect. The normal sleep architecture may be altered ([[REM sleep]] depression). Trihexyphenidyl may lower the seizure-threshold.
* Peripheral side effects: dry mouth, impaired sweating, abdominal discomfort, [[nausea]], and [[constipation]] are frequent. [[Tachycardia]] or heart palpitations (fast heart rate) may be noted. Allergic reactions are rare, but may occur. Many of these peripheral symptoms, especially considering an acute increase in anxiety with various physical complaints, as well as evidence of orthostatic hypotension and tachycardia are indicative of [[Drug withdrawal|withdrawal]], especially in people with psychiatric conditions <ref>{{cite web | title = Trihexyphenidyl
| url = http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+144-11-6 | work = Toxnet }} {{dead link|date=February 2024}}</ref>
* Eyes: trihexyphenidyl causes [[mydriasis]] with or without [[photophobia]]. It may precipitate narrow angle glaucoma or cause blurred vision.
* Tolerance may develop during therapy which requires dose adjustments.
* Striated musculature and weight gain.

Trihexyphenidyl is a [[pregnancy category]] C drug. It is advised to only use with caution if benefits outweigh risks.<ref>{{cite web|title=trihexyphenidyl (Rx)|url=http://reference.medscape.com/drug/trihexyphenidyl-343054#6|website=Medscape}}</ref>

== Overdose ==
{{more medical citations needed|section|date=May 2017}}
Trihexyphenidyl and other antiparkinsonian drugs are known to be substances of abuse. This is true both in  [[Polysubstance dependence|abusers of other substances]] and in chronic schizophrenics, the latter being infrequent abusers of other drugs.<ref name="Chiappini">{{cite journal | vauthors = Chiappini S, Mosca A, Miuli A, Semeraro FM, Mancusi G, Santovito MC, Di Carlo F, Pettorruso M, Guirguis A, Corkery JM, Martinotti G, Schifano F, Di Giannantonio M | title = Misuse of Anticholinergic Medications: A Systematic Review | journal = Biomedicines | volume = 10 | issue = 2 | pages = 355 | date = February 2022 | pmid = 35203563 | pmc = 8962297 | doi = 10.3390/biomedicines10020355 | doi-access = free }}</ref>

Overdose mimics an [[Anticholinergic#Toxicity|atropine intoxication]] with dryness of mucous membranes, red face, bowel and bladder paralysis, and [[hyperthermia]] in high doses. Central nervous system consequences are agitation, confusion, and hallucinations. An untreated overdose may be fatal, particularly in children. Premortal signs are [[respiratory depression]], arrhythmia and [[cardiac arrest]].

A specific antagonist is [[physostigmine]], which combines a peripheral and a central action.

[[Carbachol]] can be used to treat atonic bowel and bladder. It may be necessary to treat hyperthermia with cooling blankets.

A case report of 24 hour long arrhythmia was treated with [[verapamil]].<ref>{{cite journal | vauthors = Liao WB, Bullard MJ, Kuo CT, Hsiao CT, Chu PH, Chiang CW | title = Anticholinergic overdose induced torsade de pointes successfully treated with verapamil | journal = Japanese Heart Journal | volume = 37 | issue = 6 | pages = 925–931 | date = November 1996 | pmid = 9057687 | doi = 10.1536/ihj.37.925 }}</ref>

Excessive [[myoclonus]] can be complicated by [[rhabdomyolysis]]; in one case risk  was increased due to concomitant use of [[risperidone]].<ref>{{cite journal | vauthors = Hsu YC, Yeh YW | title = Multidrug overdose-induced myoclonus complicated by rhabdomyolysis: possible role and mechanism of muscle toxicity of risperidone | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 39 | issue = 6 | pages = 698–700 | date = December 2014 | pmid = 25203795 | doi = 10.1111/jcpt.12205 | doi-access = free }}</ref>

== Interactions ==
{{more medical citations needed|section|date=May 2017}}
* Other anticholinergic drugs (e.g. spasmolytics, [[antihistamine]]s, TCAs) : Side effects of trihexyphenidyl may be increased.
* [[Quinidine]] : Increased anticholinergic action (particular on AV conduction).
* Antipsychotics : Long term use of trihexyphenidyl  may mask or increase the risk of [[tardive dyskinesia]].
* [[Pethidine]] (meperidine) : Central effects and side effects of pethidine may be increased.
* [[Metoclopramide]] : Action of metoclopramide is decreased.
* Alcohol : Risk of serious intoxication.

== Pharmacology ==
=== Pharmacodynamics ===
Trihexyphenidyl is an [[anticholinergic]].<ref name="LakstygalKolesnikovaKhatsko2019" /> It is specifically an [[antimuscarinic]] and acts as a [[binding selectivity|non-selective]] [[receptor antagonist|antagonist]] of all five [[muscarinic acetylcholine receptor]]s.<ref name="LakstygalKolesnikovaKhatsko2019">{{cite journal | vauthors = Lakstygal AM, Kolesnikova TO, Khatsko SL, Zabegalov KN, Volgin AD, Demin KA, Shevyrin VA, Wappler-Guzzetta EA, Kalueff AV | title = DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens | journal = ACS Chem Neurosci | volume = 10 | issue = 5 | pages = 2144–2159 | date = May 2019 | pmid = 30566832 | doi = 10.1021/acschemneuro.8b00615 | url = }}</ref> However, its antagonistic activity is much stronger at the muscarinic acetylcholine [[M1 receptor|M<sub>1</sub>]] and [[M4 receptor|M<sub>4</sub> receptor]]s, and it can be described as [[binding selectivity|selective]] for these receptors.<ref name="LakstygalKolesnikovaKhatsko2019" /><ref name="GiachettiGIraldoLadinsky1986">{{cite journal | vauthors = Giachetti A, Giraldo E, Ladinsky H, Montagna E | title = Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine | journal = Br J Pharmacol | volume = 89 | issue = 1 | pages = 83–90 | date = September 1986 | pmid = 2432979 | pmc = 1917044 | doi = 10.1111/j.1476-5381.1986.tb11123.x | url = }}</ref>

The exact [[mechanism of action]] in parkinsonian syndromes is not precisely understood, but it is known that trihexyphenidyl blocks efferent impulses in parasympathetically innervated structures like smooth muscles (spasmolytic activity), salivary glands, and eyes ([[mydriasis]]). In higher doses direct central inhibition of cerebral motor centers may contribute. In very high doses central toxicity as seen in [[atropine]] overdose is noted.

It possibly also binds to [[dopamine receptor]]s.<ref>{{cite journal | vauthors = Berke JD, Hyman SE | title = Addiction, dopamine, and the molecular mechanisms of memory | journal = Neuron | volume = 25 | issue = 3 | pages = 515–32 | date = March 2000 | pmid = 10774721 | doi = 10.1016/S0896-6273(00)81056-9 | s2cid = 14766533 | doi-access = free }}</ref>

===Pharmacokinetics===
Trihexyphenidyl is rapidly absorbed from the [[gastrointestinal tract]]. The onset of action is within 1 hour after oral dosing. The peak activity is noted after 2 to 3 hours.<ref>{{cite web|title=Trihexyphenidyl Hydrochloride|url=https://www.drugs.com/monograph/trihexyphenidyl-hydrochloride.html|website=Drugs.com}}</ref> The duration of action of one single dose is 6 to 12 hours in a dose dependent manner. It is excreted in the urine, probably as unchanged drug. More precise data in animals and humans have so far not been determined.<ref>Watson Laboratories Inc. trihexyphenidyl hydrochloride tablets, USP. prescribing information. Corona, CA; 2005 May.</ref><ref>{{cite book | title = AHFS drug information | veditors = McEvoy GK | chapter = Trihexyphenidyl | location = Bethesda, MD | publisher = American Society of Health-System Pharmacists | date = 2006 | pages = 1256 }}</ref>

== History ==
Trihexyphenidyl has been clinically relevant in trials pertaining to Parkinson's disease since 1949.<ref name="pmid18137284">{{cite journal | vauthors = Doshay LJ, Constable K | title = Artane therapy for parkinsonism; a preliminary study of results in 117 cases | journal = Journal of the American Medical Association | volume = 140 | issue = 17 | pages = 1317–22 | date = August 1949 | pmid = 18137284 | doi = 10.1001/jama.1949.02900520003002 }}</ref>

In the US, the FDA approved Artane, or its generic form Trihexyphenidyl HCL, only on June 25, 2003 for the clinical use of all types of parkinsonism.<ref>{{cite web | vauthors = Katz R, Feeney J, Ressler T, David P |title=Approval Package for Application No. 6-773/36 |url= https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/006773_S036_ARTANE.pdf |archive-url= https://web.archive.org/web/20170211053140/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/006773_S036_ARTANE.pdf |url-status= dead |archive-date= February 11, 2017 |website=Access Data from the Food and Drug Association |publisher=FDA |access-date=8 May 2017 }}</ref>

==Society and culture==
=== Recreational use ===

The neurologist [[Oliver Sacks]] reported using the drug recreationally in the 1960s.<ref>{{citation |url=https://www.theguardian.com/science/blog/2012/oct/30/oliver-sacks-shares-hallucinations |title=Oliver Sacks shares his hallucinations |publisher=Guardian |date=2012-10-30|newspaper=The Guardian | vauthors = Smith K }}</ref> He recalled taking "a large dose" knowing full well the drug was intended for people with Parkinson's. More recounts of Dr. Sacks' experiences {{mdash}} including experimentation with [[mescaline]], [[psilocybin]], [[LSD]], and probably [[N,N-Dimethyltryptamine|DMT]]<ref>{{cite book | vauthors = Sacks O |title=Hallucinations |date=2012 |publisher=Random House Inc. |chapter = Chapter 6 }}</ref> {{mdash}} have been compared in his book ''[[Hallucinations (book)|Hallucinations]]''.

During the 1970s, trihexyphenidyl (trade name Parkan) was the most popular recreationally used prescription drug in [[Hungary]].<ref>{{cite web |url=https://mult-kor.hu/20111119_kabitoszerfogyasztas_a_szocialista_idoszakban |title=Kábítószerek a szocializmusban |trans-title=Drug use in socialist Hungary | vauthors = Sándor B, József R, Zsófia TE |website=Múlt-kor|date=19 November 2011 }}
</ref>

In a 2008 news report, trihexyphenidyl was seen to be used for recreational purposes among Iraqi soldiers and police, among other prescription drugs. The report states that the drugs were taken to relieve [[combat stress reaction]].<ref>{{cite web | vauthors = Al-Husaini M, Goode E |url= https://www.nytimes.com/2008/12/21/world/middleeast/21drugs.html?pagewanted=all |title=Abuse of Prescription Drugs Rises Among Stressed Iraqi Soldiers | work = [[The New York Times]] |date=2008-12-20 }}</ref> Although that may be the case for some, others used Artane as a substitute or more intense version of LSD. This was especially prevalent in the 1960s, according to a report in "The New Yorker". Similarly to those in Iraqi forces, some of the appeal was that the individual may retain partial control while under the influence.<ref>{{cite magazine | vauthors = Sacks O |title=Altered States |url=http://www.newyorker.com/magazine/2012/08/27/altered-states-3 |magazine=The New Yorker |date=20 August 2012 |publisher=Condé Nast |access-date=7 May 2017 }}</ref> It is still diverted from its primary use, in combination with other drugs, on the [[Réunion]] island ([[France]]).<ref>{{cite journal | vauthors = Guyon J, Maillot A, Bastard S, Weisse F, Daveluy A, Mété D | title = Psychoactive cocktail consumption on Reunion Island: A case report | journal = Journal of Analytical Toxicology | pages = 369–373 | date = February 2025 | volume = 49 | issue = 5 | pmid = 39953779 | doi = 10.1093/jat/bkaf009 }}</ref>

==Chemistry==
Trihexyphenidyl can be synthesized in two ways, one linear and one convergent synthesis.

In the first way, the initial 2-(1-piperidino)propiophenone is synthesized in turn by the aminomethylation of [[acetophenone]] using [[paraformaldehyde]] and [[piperidine]] in a [[Mannich reaction]]. In the second step the 2-(1-piperidino)propiophenone is reacted with cyclohexylmagnesium bromide in a [[Grignard reaction]].<ref>{{cite journal | vauthors = Weiss MJ, O'Donoghue MD | title = Synthesis of Certain 3-Hydroxy-3-phenylpropylsulfonium Salts. Sulfonium Analogs of Artane (Trihexyphenidyl) and Pathilon (Tridihexethyl Iodide). | journal = Journal of the American Chemical Society | date = September 1957 | volume = 79 | issue = 17 | pages = 4771–6 | doi = 10.1021/ja01574a048 | bibcode = 1957JAChS..79.4771W }}</ref>
[[File:Artane Synthesis.jpg|class=skin-invert-image|thumb|left|500px|Artane linear and convergent synthesis]]{{clear left}}

=== Stereochemistry ===
Trihexyphenidyl has a [[chiral center]] and two [[enantiomers]]. Medications are [[racemate]]s.<ref name="Rote Liste">{{cite book | author = Rote Liste Service GmbH (Hrsg.) | title = Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte) | publisher = Rote Liste Service GmbH | location = Frankfurt/Main | date = 2017 | volume = 57 | isbn = 978-3-946057-10-9 | pages = 224 }}</ref>
{| class="wikitable" style="text-align:center"
|-
! colspan="2"|Enantiomers
|-
| [[File:(R)-Trihexyphenidyl Structural Formula V1.svg|class=skin-invert-image|250 px]]<br /><small> CAS number: 40520-25-0</small>
| [[File:(S)-Trihexyphenidyl Structural Formula V1.svg|class=skin-invert-image|250 px]]<br /><small> CAS number: 40520-24-9</small>
|}

== See also ==
* [[Biperiden]] (bicyclic ring)
* [[Cycrimine]] (cyclopentanyl instead of cyclohexanyl)
* [[Gamfexine]]
* [[Procyclidine]]

== References ==
{{Reflist}}

{{Antiparkinson}}
{{Hallucinogens}}
{{Muscarinic acetylcholine receptor modulators}}
{{HHS content|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+144-11-6|title = Toxnet:Trihexyphenidyl|access-date=8 May 2017}}

[[Category:1-Piperidinyl compounds]]
[[Category:Cyclohexyl compounds]]
[[Category:M1 receptor antagonists]]
[[Category:M2 receptor antagonists]]
[[Category:M3 receptor antagonists]]
[[Category:M4 receptor antagonists]]
[[Category:Tertiary alcohols]]