Trihexyphenidyl

Trihexyphenidyl (Artane, Apo-Trihex), also known as benzhexol, 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

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 Tremors.

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.

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 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.

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

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].

Dosage forms

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

Chemistry

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. ^[5][6][7][8]

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

External links

"Trihexyphenidyl". mentalhealth.com. http://www.mentalhealth.com/drug/p30-t04.html.