VA Class:AU350

AHFS Class:

• Anticholinergic Agents 28:36.08

Generic Name(s):

• Trihexyphenidyl Hydrochloride

Trihexyphenidyl is an antimuscarinic antiparkinsonian agent.

Parkinsonian Syndrome

Trihexyphenidyl hydrochloride is used for the symptomatic management of all forms of parkinsonian syndrome including idiopathic parkinson disease and parkinsonism resulting from encephalitis (postencephalitic parkinsonism) or cerebral arteriosclerosis.123,157,200,201

Anticholinergic agents (e.g., trihexyphenidyl, benztropine) have been used as monotherapy or adjunctive therapy to other antiparkinsonian agents in the management of parkinson disease.123,157,158 Levodopa (in combination with carbidopa) is currently the most effective drug for relieving motor symptoms of the disease.101,115,157 However, the effectiveness of levodopa decreases over time and most patients develop motor complications (e.g., motor fluctuations, dyskinesias) with long-term use.115,123,157 To avoid these complications, other antiparkinsonian agents may be initiated first to postpone the use of levodopa; this strategy is generally considered for younger patients who have mild and tolerable clinical manifestations.115,123,157 Some clinicians state that anticholinergic agents may be particularly useful for initial therapy in patients younger than 60 years of age with resting tremors as their only or most prominent parkinsonian symptom.115,123 Although the main indication for anticholinergic agents in patients with parkinson disease is to control tremors, evidence of a benefit is largely anecdotal and not supported by randomized controlled studies.123,157,158 In addition, these drugs are associated with adverse neuropsychiatric and cognitive effects, which are likely to be more severe in geriatric patients.158,159 (See Cautions: Precautions and Contraindications.)

As with other antiparkinsonian drugs, tolerance to trihexyphenidyl may develop during prolonged use. The maximum therapeutic response attainable with trihexyphenidyl is in the range of 20-30% symptomatic improvement in 50-75% of patients.

For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.

Drug-induced Extrapyramidal Reactions

Trihexyphenidyl is also used for the relief of antipsychotic agent-induced (e.g., butyrophenones, phenothiazines, thioxanthenes) extrapyramidal symptoms (EPS).160,200,201

Anticholinergic agents (e.g., trihexyphenidyl, benztropine) have been used traditionally to restore the balance between acetylcholine and dopamine in patients with antipsychotic-induced EPS; however, evidence supporting a benefit is either lacking or inconsistent and the drugs are associated with a variety of adverse effects.160,161,162 For these reasons, anticholinergic agents should generally be used cautiously and for the minimum duration necessary to control EPS.160,162

Other Uses

Clinical results from preliminary trials with trihexyphenidyl in the treatment of other dyskinesias†, Huntington's chorea†, spasmodic torticollis†, and associated disorders† have been equivocal. The drug generally is not helpful in spastic states† such as cerebral palsy and hemiplegia.

Administration

Trihexyphenidyl hydrochloride is administered orally (as tablets or oral solution).200,201 Tolerability may be increased if the total daily dosage is divided and given 3 times daily with meals.200,201 Higher dosages (exceeding 10 mg daily) may be divided into 4 doses; if a fourth dose is necessary, it should be given at bedtime.200,201

If trihexyphenidyl produces excessive xerostomia, the drug should be given preferably before meals, unless nausea is a problem.200,201 In patients prone to excessive salivation, it may be preferable to administer the drug after meals.200,201 If xerostomia occurs when trihexyphenidyl is taken after a meal, mint candies, chewing gum, water, or a saliva substitute may be used to alleviate this effect.200,201

Dosage

Dosage of trihexyphenidyl hydrochloride is expressed in terms of the salt.200,201

Dosage of trihexyphenidyl hydrochloride must be carefully adjusted according to individual requirements and response, especially in patients older than 60 years of age.200,201 Therapy should be initiated with a low dosage and then the dosage should be increased gradually to the desired effect.200,201

Parkinsonian Syndrome

For the symptomatic relief of parkinsonian syndrome, the usual initial dosage of trihexyphenidyl hydrochloride is 1 mg on the first day.200,201 Subsequent dosage may be increased by 2-mg increments at 3- to 5-day intervals until a total dosage of 6-10 mg daily is achieved.200,201 The usual maintenance dosage is 2 mg 3 times daily in patients with parkinson disease.123 In patients with postencephalitic parkinsonism, dosages of up to 12-15 mg daily may be necessary.200,201

When trihexyphenidyl and levodopa are used concomitantly, consideration should be given to reducing the dosage of both drugs according to patient response and tolerance.200,201 A trihexyphenidyl hydrochloride dosage of 3-6 mg daily in divided doses usually is adequate.200,201

When transitioning from another antimuscarinic to trihexyphenidyl therapy, dosage of trihexyphenidyl should be gradually increased while dosage of the other drug is gradually decreased.200,201

Drug-Induced Extrapyramidal Reactions

The usual dosage of trihexyphenidyl for the relief of antipsychotic agent-induced extrapyramidal symptoms (EPS) may range from 2-15 mg daily.160,200,201 An initial dose of 1 mg may control some reactions; however, if extrapyramidal manifestations are not controlled within a few hours, subsequent doses may be progressively increased until adequate response is achieved.200,201 Alternatively, more rapid control may be achieved by reducing the dosage of the drug causing the reaction, then adjusting the dosage of both drugs to attain the desired drug effect without extrapyramidal symptoms.200,201 Once control of EPS has been maintained for several days, dosage of trihexyphenidyl may be reduced or discontinued.200,201

Adverse Effects

Adverse reactions to trihexyphenidyl are mainly extensions of its anticholinergic effects. (See Cautions: Adverse Effects, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.) Adverse effects of trihexyphenidyl, which are experienced by 30-50% of patients receiving the drug, may include dryness of the mouth, dizziness, blurred vision, nausea, and nervousness. Other adverse effects typical of those produced by antimuscarinic drugs include constipation, tachycardia, mydriasis, urinary hesitancy or retention, drowsiness, increased intraocular tension, weakness, vomiting, and headache. CNS stimulation, usually manifested by restlessness, agitation, confusion, delirium, and hallucination or euphoria may occur with high dosage, or in individuals with a history of hypersensitivity to other drugs, or in patients with arteriosclerosis.

Isolated instances of rashes, dilatation of the colon, paralytic ileus, and suppurative parotitis secondary to dryness of the mouth have been reported. Angle-closure glaucoma has reportedly occurred in patients receiving prolonged therapy with trihexyphenidyl. Rarely, psychiatric disturbances such as delusion, amnesia, depersonalization, a sense of unreality, and one possible case of paranoia have been reported with trihexyphenidyl.

The incidence and severity of adverse effects are generally dose related and adverse effects may occasionally be obviated by reduction in dosage. If a severe reaction occurs, the drug should be discontinued for several days and then readministered at a lower dosage.

Precautions and Contraindications

Trihexyphenidyl should be used with caution or may be contraindicated in patients with conditions in which anticholinergic effects are undesirable. The usual precautions and contraindications associated with antimuscarinics should be observed with trihexyphenidyl.

Because of the risk of adverse effects and the availability of more effective treatments, experts state that trihexyphenidyl should not be used in geriatric patients.157,159

Patients should receive a gonioscopic examination prior to initiation of trihexyphenidyl therapy. Intraocular pressure should be monitored at regular intervals during prolonged therapy with the drug.

Trihexyphenidyl hydrochloride is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.201

Some manufacturers state that the drug is also contraindicated in patients with narrow angle glaucoma.201 Blindness after long-term use due to narrow angle glaucoma has been reported.201

Pharmacology

In common with other antimuscarinic agents, trihexyphenidyl produces an atropine-like blocking action on parasympathetic-innervated peripheral structures, including smooth muscle. In addition, trihexyphenidyl exhibits a direct spasmolytic action on smooth muscle and exhibits weak mydriatic, antisialagogue, and cardiovagal blocking effects.

The exact mechanism of action of trihexyphenidyl in parkinsonian syndrome is not understood but may result from blockade of efferent impulses and from central inhibition of cerebral motor centers. In small doses, trihexyphenidyl depresses the CNS but larger doses cause cerebral excitement resembling the signs of atropine toxicity.

Pharmacokinetics

Trihexyphenidyl is rapidly absorbed from the GI tract. Following oral administration of trihexyphenidyl hydrochloride tablets, the onset of action occurs within 1 hour, peak effects last 2-3 hours, and the duration of action is 6-12 hours. The metabolic fate of trihexyphenidyl has not been determined; the drug is excreted in the urine, probably as unchanged drug.

Chemistry and Stability

Chemistry

Trihexyphenidyl hydrochloride is a synthetic tertiary amine antimuscarinic antiparkinsonian agent. The drug occurs as a white or slightly off-white, crystalline powder with not more than a very faint odor, and has solubilities of 10 mg/mL in water and 59 mg/mL in alcohol. Trihexyphenidyl hydrochloride has a bitter taste that is followed by local tingling and numbness in the mouth.

Stability

Trihexyphenidyl hydrochloride tablets and oral solution should be stored in tight containers at controlled room temperature (20-25°C).200,201 Trihexyphenidyl is incompatible with oxidizing agents.

Additional Information

For further information on pharmacology, cautions, acute toxicity, and drug interactions of trihexyphenidyl, see the Antimuscarinics/Antispasmodics General Statement 12:08.08.

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162. Ogino S, Miyamoto S, Miyake N et al. Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function. Psychiatry Clin Neurosci . 2014; 68:37-49. [PubMed 24102938]

200. Actavis. Trihexyphenidyl hydrochloride tablets prescribing information. Parsippany, NJ; 2015 Jun.

201. Mikart. Trihexyphenidyl hydrochloride oral solution prescribing information. Atlanta, GA; 2019 July.