Trihexyphenidyl

Trihexyphenidyl

File:Trihexyphenidyl.png
File:Trihexyphenidyl ball-and-stick.png
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
Legal status	Rx-Only (US)
Routes of administration	Oral, as tablet or elixir
Pharmacokinetic data
Biological half-life	3.3-4.1 hours
Identifiers
CAS Number	144-11-6 Y
ATC code	N04AA01 (WHO)
PubChem	CID: 5572
IUPHAR/BPS	7315
DrugBank	DB00376 Y
ChemSpider	5371 Y
UNII	6RC5V8B7PO Y
KEGG	D08638 Y
ChEMBL	CHEMBL1490 Y
Chemical data
Formula	C20H31NO
Molecular 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 Y Key:HWHLPVGTWGOCJO-UHFFFAOYSA-N Y
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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 and possibly the dopamine receptor.

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

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.

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.

The neurologist Oliver Sacks reports using the drug recreationally in the 1960s.

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.

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Trihexyphenidyl Syntheses

See also

• Cycrimine (cyclopentanyl instead of cyclohexanyl)
• Biperidin (bicyclic ring)
• Procyclidine
• Gamfexine