Trihexyphenidyl: Wikis

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Trihexyphenidyl
Systematic (IUPAC) name
1-cyclohexyl-1-phenyl-3-(1-piperidyl)propan-1-ol
Identifiers
CAS number 144-11-6
ATC code N04AA01
PubChem 5572
DrugBank APRD00070
Chemical data
Formula C 20H31NO 
Mol. mass 301.466 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life 3.3-4.1 hours
Excretion  ?
Therapeutic considerations
Pregnancy cat. C US
Legal status Rx-Only (US)
Routes Oral, as tablet or elixir
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Trihexyphenidyl (Artane, Apo-Trihex), also known as benzhexol, is an antiparkinsonian agent of the antimuscarinic class -- specifically at equivalent doses it has 83 per cent of the antimuscarinic power of atropine. It was invented in the United States in 1949, and it has been in clinical usage for decades. Chemically, it is a tertiary amine with alcohol, phenyl, and cyclohexyl moieties. The drug is available as the hydrochloride salt.

Contents

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]

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.

Established 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.

Therapeutic prospects

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'.

Investigational uses

Equivocal preleminary results from small studies exist for:

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.
  • Trihexyphenidyl has been reported as a drug of abuse, and while this is uncommon it may be prudent to be cautious in prescribing this drug to patients with a history of drug addiction. The drug has euphoriant and aphrodisiac properties and is smoked, insufflated, swallowed, or dissolved under the tongue and has enhanced activity when injected. Some users report a rush in the genital area when used in such a way as to deliver the dose very quickly and for this and other reasons Artane and similar drugs are referred to by some as Sexy Trihexy, Tri-Sexual, T. Hex, and Octane.
  • Patients should allow a period to adjust to the dose when first adjusting to trihexyphenidyl and when the dose has been increased or added to a regimen with other drugs because acute somnolence and accumulated fatigue can make in particularly dangerous to opeate an automobile, heavy machinery or that containing hot liquids &c.

Pregnancy and lactation

The safe use of Trihexyphenidyl during pregnancy and lactation has so far not been assured.

Side effects

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

  • CNS : 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 obstipation 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.

Dosage

  • Parkinson's disease : One mg is given on the first day. Increments are usually 2 mg every 3 days until 6 to 10 mg are reached. In postencephalitic cases up to 15 mg might be necessary, but then excessive dryness of mouth or nausea could be a problem. To increase tolerability Trihexyphenidyl may be given in 3 divided doses.
  • Extrapyramidal side effects : Usually, 5 to 15 mg daily are needed in 2 or 3 divided doses. Some patients, however, are successfully treated with as little as 1 mg daily.

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

According to a recent news report, trihexyphenidyl has been used recreationally among Iraqi soldiers and police[3]. The report states that the drug, taken in high doses, results in an increased sense of well-being and decreased anxiety. Although the drug is not considered physically addictive, the report suggests that the drug may become habit forming among some users.

Dosage forms

  • Elixir, as hydrochloride: 2 mg/5 mL (480 mL)
  • Tablet, as hydrochloride: 2 mg, 5 mg

Chemistry

Linear vs Convergent syntheses. Although the convergent synthesis is used on an industry, it is uses hazardous reagents and is not as desirable as the linear procedure for small-scale preparations.

References

  1. ^ Giachetti A, Giraldo E, Ladinsky H, Montagna E (September 1986). "Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine". Br. J. Pharmacol. 89 (1): 83–90. PMID 2432979.  
  2. ^ Sanger TD, Bastian A, Brunstrom J, et al. (May 2007). "Prospective open-label clinical trial of trihexyphenidyl in children with secondary dystonia due to cerebral palsy". J. Child Neurol. 22 (5): 530–7. doi:10.1177/0883073807302601. PMID 17690057. http://jcn.sagepub.com/cgi/pmidlookup?view=long&pmid=17690057.  
  3. ^ Mudhafer Al-Husaini and Erica Goode, New York Times, Dec. 20, 2008. "Abuse of Prescription Drugs Rises Among Stressed Iraqi Soldiers"

External links

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