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a complex consisting of an organic base in association with hydrogen chloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/30 23:39:33」(JST)

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Trihexyphenidyl (Artane, Apo-Trihex, Parkin, Pacitane), also known as benzhexol and trihex, is an antiparkinsonian agent of the antimuscarinic class. It has been in clinical usage for decades.

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^[1] and possibly the dopamine receptor.^[2]

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. 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.

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. Excessive salivation may also respond. Trihexyphenidyl may improve psychotic depression and mental inertia frequently associated with Parkinson's disease and symptomatic problems caused by antipsychotic treatment.

The drug cannot cure Parkinson's disease, but may provide substantial alleviation of symptoms. An estimated 50 to 75% of patients 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.

Investigational

Equivocal preliminary results from small studies exist for:

Other dyskinesias
Huntington's chorea
Spasmodic torticollis
Dystonia^[3]

Trihexyphenidyl does not improve cerebral palsy and hemiplegia.

Contraindications and cautions

Hypersensitivity to trihexyphenidyl
Narrow angle glaucoma
Ileus
Caution : Patients with obstructive diseases of the urogenital tract, patients with a known history of seizures and those with potentially dangerous tachycardia
Patients under 18 yrs. of age should not be treated due to a lack of clinical experience.
Patients 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.

Pregnancy and lactation

The safe use of trihexyphenidyl during pregnancy and lactation has not been established.^{[citation needed]}

Side effects

Dose-dependent side effects are frequent. Particularly geriatric patients may react with confusional states or develop delirium.

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 euphoriant effect. The normal sleep architecture may be altered (REM sleep depression). Trihexyphenidyl may lower the seizure-threshold.
Peripheral side effects: blurred vision, dry mouth, impaired sweating, abdominal discomfort, and constipation are frequent. Tachycardia may be noted. Allergic skin reactions may occur. Parenteral use may cause orthostatic hypotension.
Eyes: trihexyphenidyl causes mydriasis with or without photophobia. It may precipitate narrow angle glaucoma.
Tolerance may develop during therapy which requires dose adjustments.

Interactions

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.

Overdose

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.

Recreational use

In a 2008 news report, trihexyphenidyl has been used recreationally among Iraqi soldiers and police, among other prescription drugs. The report states that the drugs were taken to relieve combat stress.^[4]

The neurologist Oliver Sacks reports using the drug recreationally in the 1960s.^[5]

The street names for trihexyphenidyl include its trade name Artane and courage, octane, Sexy Trihexy, T Rex, Tri-Sexual.

Synthesis

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.^[6]^[7]^[8]^[9]

Trihexyphenidyl Syntheses

References

^ 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.
^ 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.
^ Mudhafer Al-Husaini; Erica Goode (2008-12-20), Abuse of Prescription Drugs Rises Among Stressed Iraqi Soldiers, New York Times
^ Oliver Sacks shares his hallucinations, Guardian, 2012-10-30
^ US patent 2680115, Wayne, R. A., "Substituted tertiary-aminoalkyl carbinols", issued 1954-06-01
^ US patent 2716121, Denton, J. J., "Basic tertiary piperidino alcohols", issued 1955-08-23
^ US patent 2682543, Wilkinson, S. & Adamson, D. W., "Catalytic reduction of diphenyl-alkanolamines", issued 1954-06-29
^ GB patent 750156, Adamson, D. W. & Duffin, W., "Improvements in cyclohexyl-phenyl-amino-propanols", issued 1956-06-13

External links

Trihexyphenidyl, mentalhealth.com

UpToDate Contents

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1. ジストニアの治療 treatment of dystonia
2. 遅発性ジスキネジア：予防および治療 tardive dyskinesia prevention and treatment
3. 脳性麻痺のマネージメントおよび予後 management and prognosis of cerebral palsy
4. パーキンソン病の薬理学的治療 pharmacologic treatment of parkinson disease
5. ミオクローヌスの治療 treatment of myoclonus

English Journal

A new knock-in mouse model of l-DOPA-responsive dystonia.

Rose SJ1, Yu XY1, Heinzer AK2, Harrast P1, Fan X1, Raike RS1, Thompson VB1, Pare JF3, Weinshenker D4, Smith Y5, Jinnah HA6, Hess EJ7.
Brain : a journal of neurology.Brain.2015 Jul 27. pii: awv212. [Epub ahead of print]
Abnormal dopamine neurotransmission is associated with many different genetic and acquired dystonic disorders. For instance, mutations in genes critical for the synthesis of dopamine, including GCH1 and TH cause l-DOPA-responsive dystonia. Despite evidence that implicates abnormal dopamine neurotran
PMID 26220941

[Drooling therapy in children with neurological disorders].

Taboas-Pereira MA, Paredes-Mercado C, Alonso-Curco X, Badosa-Pages J, Muchart J, Poo P1.
Revista de neurologia.Rev Neurol.2015 Jul 16;61(2):66-70.
in

English, SpanishTITLE: Tratamiento de la sialorrea en niños con patologia neurologica.Introduccion. La sialorrea es la incapacidad para retener la saliva dentro de la boca y su progresion al tracto digestivo, y es un problema frecuente en pacientes pediatricos con patologia neurologica, por

PMID 26156441

Evaluating the effect of risperidone on speech: A cross-sectional study.

Sinha P1, Vandana VP2, Lewis NV3, Jayaram M4, Enderby P5.
Asian journal of psychiatry.Asian J Psychiatr.2015 Jun;15:51-5. doi: 10.1016/j.ajp.2015.05.005. Epub 2015 May 11.
Speech subsystems are susceptible to the effects of several factors including medications. The atypical antipsychotics can also adversely affect the speech because of its action on serotonin and dopamine neurotransmitters. The present study aims to analyze the speech characteristics associated with
PMID 26013669

Japanese Journal

日本薬局方トリヘシフェニジル塩酸塩錠の試験法の問題点--HPLC法の適用について

尾藤孝弘,山本真也,宮本憲吾 [他]
静岡県環境衛生科学研究所報告 (52), 21-23, 2009
NAID 40018798035

A Widely Applicable Electrode Sensitive to Basic Drugs Based on Poly(vinyl chloride) Membrane Plasticized with Tricresyl Phosphate

鈴木博文,中川寛,御舩正樹,斎藤寛
Chemical & pharmaceutical bulletin 41(6), 1123-1126, 1993-06-15
… The electrode showed a near-Nernstian response to chlorpromazine, trihexyphenidyl, imipramine, dibucaine, papaverine, propranolol, tetracaine, trazodone, quinidine and cinnarizine. … The determination of 50 to 3000 μg/ml of trazodone hydrochloride in a pH 4.0 acetate buffer solution showed an average recovery of 99.4% (mean standard deviation 0.7%) by direct potentiometry. …
NAID 110003630565

★リンクテーブル★

リンク元	「トリヘキシフェニジル」「ARTANE」
関連記事	「hydrochloride」「trihexyphenidyl」

「トリヘキシフェニジル」

Trihexyphenidyl
Systematic (IUPAC) name
	(RS)-1-Cyclohexyl-1-phenyl-3-(1-piperidyl)propan-1-ol
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682160
Pregnancy; category	C US;
Routes of; administration	Oral, as tablet or elixir
Legal status	Rx-Only (US);
Pharmacokinetic data
Biological half-life	3.3-4.1 hours
Identifiers
CAS Number	144-11-6
ATC code	N04AA01 (WHO)
PubChem	CID 5572
IUPHAR/BPS	7315
DrugBank	DB00376
ChemSpider	5371
UNII	6RC5V8B7PO
KEGG	D08638
ChEMBL	CHEMBL1490
Chemical data
Formula	C20H31NO
Molar mass	301.466 g/mol
	SMILES OC(c1ccccc1)(CCN2CCCCC2)C3CCCCC3 ;
	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 ; Key:HWHLPVGTWGOCJO-UHFFFAOYSA-N ;
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