Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/06/02 11:13:01」(JST)

wiki en

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.

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

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

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

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.^[11]However, it has been clinically relevant in trials pertaining to Parkinson's disease since 1949.^[12] 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.^[13] 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 1960's, 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.^[14]

The neurologist Oliver Sacks reports using the drug recreationally in the 1960s.^[15] He states to have taken upwards of twenty pills 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^[16] - 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^[17]^[18]
Trihexyphenidyl has been shown to improve cerebral palsy and hemiplegia in children.^[19]
Treatment of hypersalivation in people with Amyotrophic Lateral Sclerosis (ALS) ^[20]

References

^ 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.
^ 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. |access-date= requires |url= (help)
^ 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: Underlying Mechanisms and Diagnosis (2015): 257.
^ Carranza-del Rio, Jorge, et al. "Use of trihexyphenidyl in children with cerebral palsy." Pediatric neurology 44.3 (2011): 202-206.
^ Jeong, Ho Hyun, et al. "A Case Study on the Use of Trihexyphenidyl, Korean Medical Treatment for the Control of Sialorrhea in Patients with Amyotrophic Lateral Sclerosis (ALS)※." The Acupuncture 30.2 (2013): 73-79.

This article incorporates public domain material from the United States Department of Health and Human Services document "Toxnet:Trihexyphenidyl" (retrieved on 8 May 2017).

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

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. パーキンソン病の薬理学的治療 pharmacologic treatment of parkinson disease
4. 脳性麻痺のマネージメントおよび予後 management and prognosis of cerebral palsy
5. ミオクローヌスの治療 treatment of myoclonus

English Journal

Heat stroke during treatment with olanzapine, trihexyphenidyl, and trazodone in a patient with schizophrenia.

Lee CP1, Chen PJ1, Chang CM1.
Acta neuropsychiatrica.Acta Neuropsychiatr.2015 Dec;27(6):380-5. doi: 10.1017/neu.2015.29.
OBJECTIVE: Heat stroke is a medical emergency. Psychiatric patients are particularly susceptible to heat stroke. Therefore, awareness and preventive measures of heat stroke are important for both clinicians and patients. Case description A 49-year-old man with schizophrenia, who was under maintenanc
PMID 26503496

AF710B, a Novel M1/σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease.

Fisher A1, Bezprozvanny I, Wu L, Ryskamp DA, Bar-Ner N, Natan N, Brandeis R, Elkon H, Nahum V, Gershonov E, LaFerla FM, Medeiros R.
Neuro-degenerative diseases.Neurodegener Dis.2015 Nov 26. [Epub ahead of print]
We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and σ1 receptor agonist. AF710B exhibits an
PMID 26606130

An automated Y-maze based on a reduced instruction set computer (RISC) microcontroller for the assessment of continuous spontaneous alternation in rats.

Heredia-López FJ1, Álvarez-Cervera FJ1, Collí-Alfaro JG1, Bata-García JL1, Arankowsky-Sandoval G1, Góngora-Alfaro JL2.
Behavior research methods.Behav Res Methods.2015 Nov 12. [Epub ahead of print]
Continuous spontaneous alternation behavior (SAB) in a Y-maze is used for evaluating working memory in rodents. Here, the design of an automated Y-maze equipped with three infrared optocouplers per arm, and commanded by a reduced instruction set computer (RISC) microcontroller is described. The soft
PMID 26563396

Japanese Journal

Dropped Head Syndrome Preceding the Onset of Dementia with Lewy Bodies

Tanaka Kanta,Wada Ikko,Okunomiya Taro,Shima Atsushi,Kambe Daisuke,Shinde Akiyo,Kageyama Takashi,Suenaga Toshihiko
Internal Medicine 53(8), 883-886, 2014
… We considered dystonia as the cause of the dropped head and administered trihexyphenidyl, an anticholinergic. … Following the discontinuation of trihexyphenidyl, the psychotic symptoms decreased but still remained. …
NAID 130003392775

トリヘキシフェニジルが有効であった首下がりの1例

塩谷彩子,冨所康志,石井一弘 [他],石井亜紀子,玉岡晃
日本内科学会雑誌 100(11), 3325-3328, 2011-11-10
症例は68歳，男性．首下がりを主訴に入院した．頸部は前屈位であり，対照的に腰部は前方に突出していた．頸部後屈の筋力が保たれ，胸鎖乳突筋を含めた頸部筋群の筋緊張は亢進しており，頸部に水平方向の振戦を認めた．頸椎MRIでは高位頸髄に変形性頸椎症の所見を認めた．頸部ジストニアと診断し，塩酸トリヘキシフェニジル投与で症状は改善した．首下がりの際にはジストニアを鑑別に挙げる必要がある．
NAID 10030390679

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

Related Pictures

★リンクテーブル★

リンク元	「ムスカリン受容体拮抗薬」「トリヘキシフェニジル」「パーキンソン病治療薬」「THP」
拡張検索	「trihexyphenidylum」

「ムスカリン受容体拮抗薬」

Trihexyphenidyl
Clinical data
AHFS/Drugs.com	Monograph
MedlinePlus	a682160
Pregnancy; category	US: C (Risk not ruled out); ;
Routes of; administration	Oral, as tablet or elixir
ATC code	N04AA01 (WHO);
Legal status
Legal status	US: ℞-only;
Pharmacokinetic data
Biological half-life	3.3-4.1 hours
Identifiers
	IUPAC name (RS)-1-Cyclohexyl-1-phenyl-3-(1-piperidyl)propan-1-ol;
CAS Number	144-11-6 ;
PubChem CID	5572;
IUPHAR/BPS	7315;
DrugBank	DB00376 ;
ChemSpider	5371 ;
UNII	6RC5V8B7PO;
KEGG	D08638 ;
ChEMBL	CHEMBL1490 ;
ECHA InfoCard	100.005.105
Chemical and physical data
Formula	C20H31NO
Molar mass	301.466 g/mol
3D model (Jmol)	Interactive image;
	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 ;
(verify)