Trihexyphenidyl

Trihexyphenidyl is used for the symptomatic treatment of Parkinson's disease in mono and combination therapy.^[5] 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 50–75% of people with Parkinson's disease will react positively and experience a 20–30% symptomatic improvement. To increase therapeutic activity, trihexyphenidyl is often given concomitantly with levodopa or other antimuscarinic or antihistaminic (e.g. diphenhydramine) agents. Combination therapy with dopamine agonists such as cabergoline is also possible. This is often termed a 'multidimensional approach'.^{[medical citation needed]}

Trihexyphenidyl has also been prescribed for essential tremor and akathisia.^[6][7]

In pediatrics, it has been used for children with dystonia due to cerebral palsy,^[8][9][10] and to control drooling.^[11]

In organophosphate poisoning, trihexyphenidyl is a more effective antidote than atropine to counteract the cholinergic crisis, seizures, and neuropathology.^[12]

Equivocal preliminary results from small studies exist for other dyskinesias, Huntington's chorea, Spasmodic torticollis.^{[medical citation needed]}

Contraindications include according to the Therapeutic Goods Administration Australia from 2022:^[13]

• Hypersensitivity to trihexyphenidyl
• Narrow angle glaucoma
• Ileus (disruption of the normal propulsive ability of the intestine)
• 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 years 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.

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.^[14] People who are older or who have psychiatric conditions may become confused or develop delirium. Side effects include but are not limited to:^[15]

• 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 ^[16]
• 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.^[17]

This section needs more reliable medical references for verification or relies too heavily on primary sources. (May 2017)

Trihexyphenidyl 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.^[18]

Overdose mimics an atropine intoxication with dryness of mucous membranes, red face, bowel and bladder paralysis, and hyperthermia in high doses. Central nervous system consequences are agitation, confusion, and hallucinations. An untreated overdose may be fatal, particularly in children. Premortal signs are respiratory depression, arrhythmia 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. It may be necessary to treat hyperthermia with cooling blankets.

A case report of 24 hour long arrhythmia was treated with verapamil.^[19]

Excessive myoclonus can be complicated by rhabdomyolysis; in one case risk was increased due to concomitant use of risperidone.^[20]

This section needs more reliable medical references for verification or relies too heavily on primary sources. (May 2017)

• 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.

Trihexyphenidyl has been clinically relevant in trials pertaining to Parkinson's disease since 1949.^[27]

In the US, the FDA approved Artane, or its generic form Trihexyphenidyl HCL, only on June 25, 2003 for the clinical use of all types of parkinsonism.^[28]

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.^[35]

Stereochemistry

Trihexyphenidyl has a chiral center and two enantiomers. Medications are racemates.^[36]

More information Enantiomers ...

Enantiomers
CAS number: 40520-25-0	CAS number: 40520-24-9

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