Trihexyphenidyl works as an anticholinergic used for the treatment of tremors, spasms, stiffness, and weak muscle control seen in patients with Parkinson disease.[1] It can also be useful for the prevention or treatment of similar muscular conditions, which are caused by certain central nervous system (CNS) drugs such as fluphenazine, haloperidol, chlorpromazine. Although it has been pertinent in clinical trials investigating the treatment of Parkinson disease since 1949, it was approved for the management of all types of parkinsonism (idiopathic, postencephalitic, and arteriosclerotic) in June 2003 by the FDA.[2] Trihexyphenidyl is often used as an adjuvant therapy when treating the forms mentioned above of parkinsonism with levodopa.[2]

In 2008, there were reports that Iraqi police and soldiers were using trihexyphenidyl for recreational purposes along with other prescription drugs. Reportedly the drugs were taken as they seemed to relieve combat stress. Although this could have been the primary cause for use in some, some also seen as a substitute or a stronger version of LSD by some users.

Although the precise mechanism of action of trihexyphenidyl remains poorly understood, it appears to act on the parasympathetic nervous system by inhibiting the efferent impulses directly. Structures innervated by the parasympathetic system, such as the salivary glands, eyes, and smooth muscles (directly and indirectly), are affected, even on smaller doses. The direct central inhibition of cerebral motor centers may occur with higher doses. Researchers believe the receptors affected are the dopamine and M1 muscarinic receptors.[3][4] The drug is absorbed from the gastrointestinal tract, and the onset of action occurs 60 minutes after an oral dose with peak activity occurring after 2 to 3 hours. One dose has a duration of action of around 6 to 12 hours and is then excreted in the urine, most likely as an unchanged drug.[5]

The dosage of trihexyphenidyl HCl varies with the individual and is determined empirically. Patients start with a low initial dose, which is increased gradually, especially in adults who are older than 60 years of age. The patient can take the oral drug before or after meals; this depends on the individual patient as in those with excessive xerostomia (due to trihexyphenidyl’s anticholinergic effects) could take the drug before meals and those who feel nauseous or are prone to excessive salivation could take the drug after meals. Trihexyphenidyl is better tolerated if taken in 3 separate doses daily, with food. Higher doses, such as more than 10 mg per day, could be divided into four doses daily (one taken with each meal and one at bedtime).

Clinicians should avoid abrupt withdrawal of trihexyphenidyl in patients undergoing treatment for parkinsonism symptoms, as this could cause an acute exacerbation of existing symptoms. There are reports of neuroleptic malignant syndrome in patients who had an abrupt withdrawal of treatment.

Idiopathic Parkinsonism

For initial therapy for symptoms of idiopathic parkinsonism, 1 mg tablet of trihexyphenidyl is given on the first day. This dose could then increase by 2-mg accretions at intervals of around four days until a total dose of 6 to 10 mg is being administered daily to the patient. The final daily dose is determined by the physician, to what he deems the optimal level for symptom control. Most patients display significant improvement in symptoms on total daily doses of 6 to 10 mg, but some, especially those of the postencephalitic sub-group, could require daily doses of around 12 to 15 mg for symptom management.

Drug-Induced Parkinsonism

The optimal dose and dosing frequency of trihexyphenidyl required to control the extrapyramidal symptoms of commonly used CNS drugs, for example, thioxanthenes, and phenothiazines, are determined empirically by the physician. For most patients, the total daily dosage ranges from 5 to 15 mg, although there have been reported cases of symptoms being sufficiently controlled on as minimal as 1 mg daily. Therefore, recommendations are to start treatment with a single dose of 1 mg. Failure of the extrapyramidal manifestations to resolve in a few hours could prompt an increase in dosage until achieving satisfactory control of symptoms. Adequate control of symptoms is sometimes possible in a shorter duration by briefly decreasing the CNS drug dosage when initiating trihexyphenidyl and gradually adjusting the dose of both drugs for the desired effects without the onset of extrapyramidal symptoms.

Concomitant Use with Levodopa

The usual dose of both levodopa and trihexyphenidyl may require reduction when administering both of these drugs concomitantly. Any adjustment in dosage needs to be made carefully, depending on the level of symptom control and subsequent side effects. An adequate dosage for symptom control with minimal side effects is generally around 3 to 6 mg daily, given in divided doses.[6][7][8]

Adverse effects of trihexyphenidyl are frequently seen in a dose-dependent manner but usually decrease over time as tolerance develops, and the body adapts to the drug. Even with all of the adverse effects considered, trihexyphenidyl demonstrated dramatic and consistent improvement of neurologic defects in people of ages between 16 to 86 years, over a 5-year course. Confusion and delirium frequently occur in patients who were older than 86 years or had a psychiatric condition.

Adverse effects of trihexyphenidyl include but are not limited to:

Ocular effects: Mydriasis may present in patients with and without photophobia. This condition can lead to blurred vision or precipitate narrow-angle glaucoma by angle closure, which increases intraocular pressure.

CNS effects: Frequently reported side effects include a headache, dizziness, drowsiness, and vertigo. Anxiety, nervousness, confusion, agitation, and confusion occurred in patients who were on higher doses. Trihexyphenidyl also produces a short-acting euphoric and mood-elevating effect, and that is why it is a drug of abuse. There have been cases of the disruption of normal sleep architecture (REM sleep depression). It could also potentially lower the seizure threshold, and use requires caution in people with epilepsy or other seizure disorders.

Peripheral side effects: As with other anticholinergics, impaired sweating, dry mouth, abdominal discomfort, nausea, urinary retention, and constipation[9] are frequently seen (patients require monitoring for long-term use). Some patients also develop tachycardia. Although allergic reactions are infrequent, they could occur with the use of trihexyphenidyl. Fatal hyperthermia and severe anhidrosis are also possible, and that is why caution is advised when using the drug during exercise or in extremely hot weather.

Patients taking trihexyphenidyl have also reported weight gain.

Tolerance could develop with the prolonged use of the drug, and dosing adjustments may be necessary.

Trihexyphenidyl classifies as FDA "pregnancy risk factor class C." [10]

Trihexyphenidyl is contraindicated in those with hypersensitivity to the drug (trihexyphenidyl HCl) or any of its active ingredients.

It is also contraindicated in patients with narrow-angle glaucoma because it has anticholinergic activity that could cause mydriasis, further narrowing the angle of the lens, increasing the IOP, and worsening the condition.