Trihexyphenidyl

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Trihexyphenidyl

Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a682160
Pregnancy  US: C (Risk not ruled out)
category
Routes of
Oral, as tablet or elixir
administration
 N04AA01 (WHO)
ATC code

Legal status
 US: ℞-only
Legal status

Pharmacokinetic data
Biological half-
3.3-4.1 hours
life
Identifiers
IUPAC name[show]
 144-11-6
CAS Number

 5572
PubChem CID
  7315
IUPHAR/BPS

 DB00376
DrugBank

 5371
ChemSpider

 6RC5V8B7PO
UNII

 D08638
KEGG

 CHEMBL1490
ChEMBL

ECHA InfoCard 100.005.105

Chemical and physical data
Formula C20H31NO
Molar mass 301.466 g/mol
 Interactive image
3D model (JSmol)

SMILES[show]
InChI[show]
(verify)

Trihexyphenidyl (Artane, Apo-Trihex, Parkin, Pacitane), also known as benzhexol,

Ariane, and trihex, is an antiparkinsonian agent of the antimuscarinic class. It has been in
clinical usage for decades.[vague]

Contents
 1 Uses
 2 Contraindications
 3 Adverse effects
 4 Overdose
 5 Interactions
 6 Pharmacology
 7 Chemistry
o 7.1 Stereochemistry
 8 History
 9 Society and culture
o 9.1 Recreational use
 10 Research
 11 See also
 12 References
Uses
Trihexyphenidyl is used for the symptomatic treatment of Parkinson's disease in mono and
combination therapy. It is active in postencephalitic, arteriosclerotic, and idiopathic forms.
The drug is also commonly used to treat extrapyramidal side effects occurring during
antipsychotic treatment. It reduces the frequency and duration of oculogyric crises as well as
of 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]

The drug cannot cure Parkinson's disease, but may provide substantial alleviation of
symptoms. An estimated 50 to 75% of people with Parkinson's disease will react positively
and experience a 20 to 30% symptomatic improvement. To increase therapeutic activity
trihexyphenidyl is often given concomitantly with levodopa, other antimuscarinic or
antihistaminic (e.g. diphenhydramine) agents. Combination treatment with dopaminergic
agonists such as cabergoline is also possible. This is often termed a 'multidimensional
approach'. It has also been prescribed for essential tremor and akathisia.[medical citation needed]

Contraindications
Contradindications include:[medical citation needed]

 Hypersensitivity to trihexyphenidyl
 Narrow angle glaucoma
 Ileus
 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 yrs. 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 side effects 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.[1] People who are older or who psychiatric conditions may become
confused or develop delirium. Side effects include but are not limited to:[2]

 Central nervous system: drowsiness, 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 withdrawal, especially in people with psychiatric conditions [3]
 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.[4]

Overdose
This section needs more medical references for verification or relies too heavily
on primary sources. Please review the contents of the section and add the
appropriate references if you can. Unsourced or poorly sourced material may be
challenged and removed. (May 2017)

Trihexyphenidyl (THP) and other antiparkinsonian drugs are known to be substances of

abuse. This is true both in abusers of other substances and in chronic schizophrenics, the
latter being infrequent abusers of other drugs. Trihexyphenidyl mimics an atropine
intoxication with 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. An untreated overdose may be fatal, particularly in children. Premortal
signs are respiratory depression 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. The vital functions should be monitored and stabilized. It may be necessary to
treat hyperthermia with cooling blankets. Clinical case reports have repeatedly shown
overdose of Trihexyphenidyl alongside other substances.

Interactions
This section needs more medical references for verification or relies too heavily
on primary sources. Please review the contents of the section and add the
appropriate references if you can. Unsourced or poorly sourced material may be
challenged and removed. (May 2017)

 Other anticholinergic drugs (e.g. spasmolytics, antihistamines, 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
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 binds to the M1
muscarinic receptor[5] and possibly the dopamine receptor.[6] 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.[7] 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.[8][9]

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.[10]

Artane linear and convergent synthesis

Stereochemistry

Trihexyphenidyl contains a stereocenter and consists of two enantiomers. This is a racemate,

ie a 1: 1 mixture of ( R ) - and the ( S ) - form:[11]

Enantiomers of trihexyphenidyl

CAS number: 40520-25-0 CAS number: 40520-24-9

History
Artane, or its generic form Trihexyphenidyl HCL, was approved by the FDA on June 25th,
2003 for the clinical use of all types of parkinsonism.[12] However, it has been clinically
relevant in trials pertaining to Parkinson's disease since 1949.[13] Artane is an anticholinergic
drug which is prescribed by doctors throughout the world. It is also abused, typically in
combination with other drugs or delicate pharmaceutical agents. Prisons in Iraq were among
the places where abuse was obvious, along with within communities of Iraqi soldiers.[citation
needed]

Society and culture

Recreational use

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.[14] 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.[15]

The neurologist Oliver Sacks reports using the drug recreationally in the 1960s.[16] He
recalled taking "a large dose" knowing full well the drug was intended for people with
Parkinson's. More recounts of Dr. Sack's experiences - including experimentation with
mescaline, psilocybin, LSD, and probably DMT [17] - have been compared in his novel
Hallucinations (book).

Research
Equivocal preliminary results from small studies exist for:

 Other dyskinesias
 Huntington's chorea
 Spasmodic torticollis
 Dystonia[18][19]

See also
 Biperiden (bicyclic ring)
 Cycrimine (cyclopentanyl instead of cyclohexanyl)
 Gamfexine
 Procyclidine

References
1.

 Doshay, L. J., K. Constable, and A. Zier. "Five year follow-up of treatment with
trihexyphenidyl (Artane): Outcome in four hundred eleven cases of paralysis agitans."
Journal of the American Medical Association 154.16 (1954): 1334-1336.
  "Trihexyphenidyl". Web MD. First Databank Inc.
  TRIHEXYPHENIDYL http://toxnet.nlm.nih.gov/cgi-
bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+144-11-6
  "trihexyphenidyl (Rx)". Medscape.
  Giachetti, A.; Giraldo, E.; Ladinsky, H.; Montagna, E. (1986). "Binding and functional
profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and
dicyclomine". British Journal of Pharmacology. 89 (1): 83–90. doi:10.1111/j.1476-
5381.1986.tb11123.x. PMC 1917044  . PMID 2432979.
  Berke, J. D.; Hyman, S. E. (2000). "Addiction, dopamine, and the molecular mechanisms
of memory". Neuron. 25 (3): 515–532. doi:10.1016/S0896-6273(00)81056-9.
PMID 10774721.
  "Trihexyphenidyl Hydrochloride". Drugs.com.
  Watson Laboratories Inc. trihexyphenidyl hydrochloride tablets, USP. prescribing
information. Corona, CA; 2005 May.
  AHFS drug information 2006. McEvoy GK, ed. Trihexyphenidyl. Bethesda, MD:
American Society of Health-System Pharmacists; 2006:1256.
  Weiss, Martin J., and Maurice D. O'Donoghue. "Synthesis of Certain 3-Hydroxy-3-
phenylpropylsulfonium Salts. Sulfonium Analogs of Artane (Trihexyphenidyl) and Pathilon
(Tridihexethyl Iodide)." Journal of the American Chemical Society 79.17 (1957): 4771-4776.
  Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für
Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste
Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 224.
  Katz, Russell; Feeney, John; Ressler, Timothy; David, Paul. "Approval Package for
Application No. 6-773/36" (PDF). Access Data from the Food and Drug Association. FDA.
Retrieved 8 May 2017.
  Doshay, L. J., and Constable, K.: Artane Therapy for Parkinsonism, J.A.M.A. 140:1317
(Aug. 27) 1949
  Mudhafer Al-Husaini; Erica Goode (2008-12-20), Abuse of Prescription Drugs Rises
Among Stressed Iraqi Soldiers, New York Times
  Sacks, Oliver. "Altered States". The New Yorker. Condé Nast. Retrieved 7 May 2017.
  Oliver Sacks shares his hallucinations, Guardian, 2012-10-30
  Sacks, Oliver (2012). Hallucinations. Ch. 6: Random House Inc.
  Sanger, T. D.; Bastian, A.; Brunstrom, J.; Damiano, D.; Delgado, M.; Dure, L.;
Gaebler-Spira, D.; Hoon, A.; Mink, J. W.; Sherman-Levine, S.; Welty, L. J.; Child Motor
Study, G. (2007). "Prospective Open-Label Clinical Trial of Trihexyphenidyl in Children with
Secondary Dystonia due to Cerebral Palsy". Journal of Child Neurology. 22 (5): 530–537.
doi:10.1177/0883073807302601. PMID 17690057.
 Tarnopolsky, Mark, and Rashid Alshahoumi. "Complex I Deficiency." Mitochondrial Case
Studies: Underlyi