Trihexyphenidyl

Mechanism of Action

The precise mechanism of action of trihexyphenidyl is not completely understood; it appears to act on the parasympathetic nervous system by inhibiting efferent impulses directly. Structures innervated by the parasympathetic system, such as the salivary glands, eyes, and smooth muscles (directly and indirectly), are affected even at smaller doses. The direct central inhibition of cerebral motor centers may occur with higher doses. Research suggests that the dopamine and M1 muscarinic receptors are affected.[9][10]

Pharmacokinetics

Absorption: The drug is well absorbed from the gastrointestinal tract. The onset of action occurs 60 minutes after an oral dose, with peak activity occurring after 2 hours.

Distribution: Trihexyphenidyl achieves high concentration in the brain, facilitated by intralysosomal uptake.

Metabolism: Trihexyphenidyl is metabolized by hydroxylation of the alicyclic groups. Enterohepatic circulation is low.

Excretion: The estimated elimination half-life in adults is about 5 to 10 hours, but some studies suggest an elimination half-life of up to 33 hours.[3]

Administration

Available Dosage Forms and Strengths

Trihexyphenidyl is available as 2 mg and 5 mg oral tablets and as a solution of 2 mg/5 mL.[11] The dosage of trihexyphenidyl HCl varies with the individual and is determined empirically. Clinicians should prescribe a low initial dose and increase the dose gradually, especially in adults older than 60. The patient can take the oral drug before or after meals; those with excessive xerostomia (due to trihexyphenidyl's anticholinergic effects) can take the medication before meals, and those prone to nausea or excessive salivation can take the drug after meals. Trihexyphenidyl is better tolerated with food in 3 separate doses daily. Higher doses, such as more than 10 mg/d, could be divided into 4 doses daily (1 taken with each meal and 1 at bedtime).

Adult Dosage

Idiopathic Parkinsonism

As initial therapy for 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 4 days until a total dose of 6 to 10 mg is administered daily to the patient. The clinician determines the final daily optimal dosage for symptom control. Most patients show significant symptom improvement on 6 to 10 mg daily. Still, some postencephalitic patients could require daily doses of around 12 to 15 mg for symptom management.[12] 

According to American Academy of Neurology guidelines, anticholinergics (including trihexyphenidyl) should be prescribed only if the tremor is predominant.[13] According to NICE guidelines, anticholinergics should not be used in patients with predominant dyskinesia or motor fluctuations.[14] According to the International Parkinson and Movement Disorder Society guidelines, anticholinergics are clinically used for younger patients with no cognitive impairment.[15] 

Drug-Induced Parkinsonism

The optimal dose and dosing frequency of trihexyphenidyl required to control the extrapyramidal symptoms of commonly used CNS drugs, such as thioxanthenes and phenothiazines, is determined empirically by the clinician. The total daily dosage ranges from 5 to 15 mg for most patients, although there have been reported cases of symptoms being sufficiently controlled on as minimal as 1 mg daily. Therefore, the recommendation is 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 adequate 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.[16] 

American Psychiatry Association guidelines (APA 2020) suggest that patients with acute dystonia due to antipsychotic therapy be treated with anticholinergic medication like trihexyphenidyl. In addition, APA suggests that for drug-induced parkinsonism due to antipsychotic treatment, reduce the dose of the antipsychotic drug, change to another antipsychotic drug, or treat with anticholinergic medications.[17]

Concomitant Use with Levodopa

The usual dose of 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 adverse effects. An adequate dosage for symptom control with minimal adverse effects is generally around 3 to 6 mg daily, given in divided doses.[7]

Specific Patient Population

Hepatic impairment: The manufacturer's labeling does not provide information regarding dose adjustment for hepatic impairment. Use with caution.

Renal impairment: The manufacturer's labeling does not provide information regarding dose adjustment for renal impairment. Use with caution.

Pregnancy considerations: Trihexyphenidyl crosses the placenta and is classified as a former FDA pregnancy risk factor class C medication. Miscarriage and molar pregnancy have been reported. In a cohort of 2323 patients exposed to anticholinergics drugs, significant congenital disabilities were not increased. However, miscarriage and molar pregnancy have been reported in a few cases. Use with caution.[11]

Breastfeeding considerations: Prolonged trihexyphenidyl use may suppress lactation, but a single dose is not likely to interrupt breastfeeding. During long-term use, clinicians should monitor for signs of decreased lactation.[12]

Older patients (potentially inappropriate medicine): According to the American Geriatric Society (Beers criteria), trihexyphenidyl is a PIM for use in older adults. Older adults have an increased risk of anticholinergic adverse effects like cognitive impairment, confusion, delirium, constipation, and urinary retention. Trihexyphenidyl is also not recommended to manage antipsychotic drug-associated extrapyramidal effects in older adults. Consequently, older patients should be prescribed lower doses of trihexyphenidyl and monitored closely.[18] One case report indicated that trihexyphenidyl improves apraxia of eyelid opening seen in Parkinson disease; further research is required.[19]

Pediatric patients: Trihexyphenidyl is used off-label to treat dystonia and can also reduce drooling/sialorrhea in children with developmental disabilities.[8][20][21]

Adverse Effects

Adverse effects of trihexyphenidyl are frequently dose-dependent 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 between the ages of 16 and 86 over a 5-year course. Confusion and delirium frequently occur in older patients or patients with psychiatric disorders. 

Adverse effects of trihexyphenidyl according to system organ classification (SOC) 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.[22]

CNS effects: Frequently reported adverse effects include headache, dizziness, drowsiness, and vertigo. Anxiety, nervousness, confusion, and agitation occurred in patients on higher doses. Trihexyphenidyl also causes a short-acting euphoric and mood-elevating effect, which is why it is a drug of potential misuse.[23] Additionally, there have been cases involving disruption of normal sleep architecture (REM sleep depression). Trihexyphenidyl may also lower the seizure threshold, requiring caution in people with epilepsy or other seizure disorders.[24] Long-term use has the potential to develop Alzheimer's disease in preclinical studies.[25]

Peripheral adverse effects: As with other anticholinergics, impaired sweating, dry mouth, abdominal discomfort, nausea, urinary retention, and constipation are frequently seen (patients require monitoring for long-term use).[26] Some patients also develop tachycardia. Although allergic reactions are infrequent, they can occur with trihexyphenidyl use. Fatal hyperthermia and severe anhidrosis are also possible, so caution is advised when using the drug during exercise or in hot weather.[27]

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

Drug-Drug Interactions

Potassium chloride is contraindicated in patients with inadequate gastric emptying. Anticholinergic agents impair motility and increase the contact time of potassium chloride with gastric mucosa, leading to gastritis, peptic ulcer, and increased risk of upper GI bleeding.[28] Severe dizziness has been reported in patients treated with rivaroxaban and trihexyphenidyl. The mechanism of this interaction is unknown.[29] Alcohol, barbiturates, cannabinoids, and opiates may have additive effects with trihexyphenidyl; concurrent use should be avoided.[30]

Contraindications

Box Warnings

Per the manufacturer's labeling, trihexyphenidyl is contraindicated in those with hypersensitivity to the drug (trihexyphenidyl HCl) or excipients. Trihexyphenidyl is also contraindicated in patients with narrow-angle glaucoma because it possesses anticholinergic activity that could cause mydriasis, further narrowing the lens angle, increasing the IOP, and worsening the condition.

Warning and Precautions

Clinicians should avoid abrupt withdrawal of trihexyphenidyl in patients undergoing treatment for Parkinsonism symptoms, as this could cause an acute exacerbation of existing symptoms. In addition, there are reports of neuroleptic malignant syndrome in patients who had an abrupt withdrawal from treatment.[31][32]

Monitoring

Trihexyphenidyl is not strictly contraindicated for patients with liver, kidney, or cardiac disorders, but recommendations are to monitor these patients closely when using the drug. Additionally, patients with hypertension should also have their blood pressure monitored regularly during therapy.

Some patients may require the indefinite use of trihexyphenidyl, and since it has properties similar to atropine, constant and long-term supervision should be implemented to prevent allergic and other unwanted reactions. Because of its parasympathetic activity, trihexyphenidyl should be used precautiously and monitored closely in patients with obstructive genitourinary or gastrointestinal diseases, glaucoma, and older males with prostatic hypertrophy.[22] Older patients commonly develop an increased sensitivity to these types of drugs and require strict regulation of their dosage.

In 2008, there were reports that Iraqi police and soldiers were using trihexyphenidyl for recreational purposes and other prescription drugs. Reportedly, the drugs were taken as they seemed to relieve combat stress. Reports indicate that trihexyphenidyl misuse can be seen in delusional disorders. Monitor for signs of misuse using prescription drug monitoring programs.[33][34][35]

Toxicity

Signs and Symptoms of Overdose

As with some other antiparkinsonian medications, trihexyphenidyl is known to be a drug of misuse. Misuse has been reported primarily in patients with chronic schizophrenia and those with other substance use disorders. A recent systematic review published in 2022 reveals an alarming trend of misuse of trihexyphenidyl. Benzhexol/Trihexyphenidyl (THP) is one of the most misused anticholinergic drugs. Trihexyphenidyl is frequently combined with benzodiazepines, alcohol, cannabis, amphetamines, opioids, LSD, PCP, nicotine, and cocaine.[23]

Trihexyphenidyl toxicity resembles atropine intoxication (antimuscarinic effects) with xerostomia, anhidrosis, mydriasis, nausea/vomiting, tachycardia, hyperpyrexia, decreased bowel and bladder movements, rash, and hyperthermia, which usually accompany excessive doses. CNS symptoms observed with overdose include confusion, restlessness, agitation, incoordination, paranoid and psychotic reactions, delirium, and hallucinations. Reports exist of CNS depression leading to coma, respiratory and circulatory failure, and death in cases of severe overdose.[36] If the overdose does not receive prompt treatment, it could be fatal, especially in younger children.[10]

Management of Overdose

The management of overdoses is always supportive; establish adequate airway patency immediately. Physostigmine is a specific antagonist that acts centrally and peripherally to counter the antimuscarinic effects. Convulsions and hyperactivity require management with diazepam, but with caution, as the risk of CNS depression could be exacerbated. Acidosis and hypoxia should have appropriate therapy. Dysrhythmias should not be treated with antiarrhythmic drugs. Atonic bladder and bowel are treatable with carbachol.

Enhancing Healthcare Team Outcomes

Clinicians usually prescribe trihexyphenidyl for specific indications such as drug-induced parkinsonism. As discussed above, neurologists, psychiatrists, and movement disorder specialists play an essential role in managing patients who require trihexyphenidyl therapy. Pharmacists should perform medication reconciliation and inform the clinicians of interactions. Nursing should monitor for compliance, signs of misuse, and clinical improvement. Clinicians (MDs, DOs, PAs, and NPs) play an important role in prescribing trihexyphenidyl and restrict its usage for only essential conditions. The utilization of prescription drug monitoring programs (PDMP) is recommended due to reported misuse of trihexyphenidyl.[37] 

In light of the recent systematic review, concomitant drug misuse is common with trihexyphenidyl; medical toxicologists should be consulted. Due to the potential toxicity of trihexyphenidyl, its dosing and management require an interprofessional healthcare team consisting of the clinician, nurse, and pharmacist monitoring the patient for complications and communicating any concerns to the healthcare team. This interprofessional approach drives better outcomes while limiting the potential for drug misuse or adverse events. A respective study suggests that direct care of patients under medical toxicologist supervision is associated with significant reductions in length of hospital stay, costs, and mortality in patients hospitalized with a drug overdose.[38]