Trihexyphenidyl

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Trihexyphenidyl
Systematic (IUPAC) name
(RS)-1-cyclohexyl-1-phenyl-3-(1-piperidyl)propan-1-ol
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa682160
Pregnancy cat.C US
Legal statusRx-Only (US)
RoutesOral, as tablet or elixir
Pharmacokinetic data
Half-life3.3-4.1 hours
Identifiers
CAS number144-11-6 YesY
ATC codeN04AA01
PubChemCID 5572
DrugBankDB00376
ChemSpider5371 YesY
UNII6RC5V8B7PO YesY
KEGGD08638 YesY
ChEMBLCHEMBL1490 YesY
Chemical data
FormulaC20H31NO 
Mol. mass301.466 g/mol
 YesY (what is this?)  (verify)
 
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Trihexyphenidyl
Systematic (IUPAC) name
(RS)-1-cyclohexyl-1-phenyl-3-(1-piperidyl)propan-1-ol
Clinical data
AHFS/Drugs.commonograph
MedlinePlusa682160
Pregnancy cat.C US
Legal statusRx-Only (US)
RoutesOral, as tablet or elixir
Pharmacokinetic data
Half-life3.3-4.1 hours
Identifiers
CAS number144-11-6 YesY
ATC codeN04AA01
PubChemCID 5572
DrugBankDB00376
ChemSpider5371 YesY
UNII6RC5V8B7PO YesY
KEGGD08638 YesY
ChEMBLCHEMBL1490 YesY
Chemical data
FormulaC20H31NO 
Mol. mass301.466 g/mol
 YesY (what is this?)  (verify)

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. The drug is available as the hydrochloride salt.

Pharmacology[edit]

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[edit]

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[edit]

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.

Investigational[edit]

Equivocal preliminary results from small studies exist for:

Trihexyphenidyl does not improve cerebral palsy and hemiplegia.

Contraindications and cautions[edit]

Pregnancy and lactation[edit]

The safe use of Trihexyphenidyl during pregnancy and lactation has not been established.

Side effects[edit]

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

Interactions[edit]

Dosage[edit]

Overdose[edit]

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[edit]

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]

Trihexyphenidyl can be used via virtually all routes of administration, and smoking it mixed into opium and chasing the dragon with morphine, heroin etc. have also been reported (see below).

As is the case with structurally-similar agents such as dicycloverine/dicyclomine (q.v.), scopolamine (q.v.), benztropine and others, there are several different groups of recreational users who use the drug for very different reasons. They could be divided into eight groups, the first of which has virtually no overlap with next six, and the last on the list is somewhat mysterious and may combine parts of the other seven, which do share the same much lower dose range and probably overlap to a high degree. Some of the uses grade off into off-label therapeutic uses, e.g. to combat excessive sweating, hasten sleep, and others. Of course, using any medication is a manner other than that intended can pose problems. In rough order of descending doses usually used, trihexyphenidyl abusers/misuers/unsupervised users can be said to be:

The street names for trihexyphenidyl include its trade name Artane® and the following, in alphabetical order: courage, octane, Sexy Trihexy, T Rex, Tri-Sexual. Except as noted elsewhere in the article, trihexyphenidyl is not as common on the street many places.

Dosage forms[edit]

Chemistry[edit]

Trihexyphenidyl, 1-cyclohexyl-1-phenyl-3-piperidineopropan-1-ol, is synthesized in two ways (linear and 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 so-called Mannich reaction. In the second step the 2-(1-piperidino)propiophenone is reacted with cyclohexylmagnesiumbromide in a Grignard reaction. [13][14][15][16]

Trihexyphenidyl Syntheses.png

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

References[edit]

  1. ^ 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. PMC 1917044. PMID 2432979.  edit
  2. ^ 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.  edit
  3. ^ 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.  edit
  4. ^ Mudhafer Al-Husaini; Erica Goode (2008-12-20), Abuse of Prescription Drugs Rises Among Stressed Iraqi Soldiers, New York Times 
  5. ^ Oliver Sacks shares his hallucinations, Guardian, 2012-10-30 
  6. ^ Chocolate To Morphine
  7. ^ Inside Narcotics, 5th Edition (2010), Ch VII
  8. ^ Inside Narcotics, 5th Edition (2010), Ch VII
  9. ^ opioids.org/
  10. ^ Morphine
  11. ^ Inside Narcotics
  12. ^ Inside Narcotics, Ch XI
  13. ^ US patent 2680115, Wayne, R. A., "Substituted tertiary-aminoalkyl carbinols", issued 1954-06-01 
  14. ^ US patent 2716121, Denton, J. J., "Basic tertiary piperidino alcohols", issued 1955-08-23 
  15. ^ US patent 2682543, Wilkinson, S. & Adamson, D. W., "Catalytic reduction of diphenyl-alkanolamines", issued 1954-06-29 
  16. ^ GB patent 750156, Adamson, D. W. & Duffin, W., "Improvements in cyclohexyl-phenyl-amino-propanols", issued 1956-06-13 

External links[edit]