Continuing Education Activity

Benztropine is classified as a synthetic muscarinic receptor antagonist, also known as an anticholinergic drug, and shares a structural resemblance with diphenhydramine and atropine. Benztropine is approved by the US Food and Drug Administration (FDA) as an adjunctive therapy for various forms of parkinsonism, including idiopathic and postencephalitic parkinsonism. This medication extends its therapeutic application beyond Parkinson disease, effectively addressing drug-induced extrapyramidal symptoms and playing a crucial role in preventing and treating acute dystonic reactions. Due to its prolonged duration of action, benztropine requires less frequent dosing than diphenhydramine.

Benztropine exerts its action in the central nervous system (CNS) and smooth muscles by competing with acetylcholine at muscarinic receptors. Consequently, it reduces central cholinergic effects by blocking muscarinic receptors, which appears to alleviate the symptoms of Parkinson disease. With a lower level of CNS stimulation than trihexyphenidyl, benztropine is the preferred drug for geriatric patients. This activity reviews the indications, mechanism of action, administration, contraindications, and adverse effects of benztropine in managing Parkinson disease. This activity is tailored to provide interprofessional healthcare team members with the knowledge necessary for making well-informed decisions regarding the use of benztropine in diverse clinical scenarios.

Objectives:

• Identify the approved indications for benztropine, recognizing its role as an adjunctive therapy in various forms of parkinsonism, including idiopathic and postencephalitic parkinsonism.

• Implement proper dosing strategies for benztropine, considering its prolonged duration of action and adjusting dosages according to individual patient needs.

• Assess patients for potential adverse effects and drug interactions associated with benztropine, emphasizing a comprehensive understanding of its impact on the central nervous system.

• Collaborate with interprofessional healthcare teams to enhance patient outcomes through coordinated efforts in managing Parkinson disease and associated conditions with benztropine.

Indications

Benztropine is a type of synthetic drug that falls under the category of muscarinic receptor antagonists, which are also known as anticholinergic drugs. Thus, the drug shares a structural resemblance with diphenhydramine and atropine. Benztropine is approved by the US Food and Drug Administration (FDA) as an adjunctive therapy for various forms of parkinsonism, including idiopathic and postencephalitic parkinsonism. This medication extends its therapeutic application beyond Parkinson disease, effectively addressing drug-induced extrapyramidal symptoms and playing a crucial role in preventing and treating acute dystonic reactions.

Due to its prolonged duration of action, benztropine requires less frequent dosing than diphenhydramine. Benztropine exerts its action in the central nervous system (CNS) and smooth muscles by competing with acetylcholine at muscarinic receptors. Consequently, it reduces central cholinergic effects by blocking muscarinic receptors, which appears to alleviate the symptoms of Parkinson disease. With a lower level of CNS stimulation than trihexyphenidyl, benztropine is the preferred drug for geriatric patients.[1] 

FDA-Approved Indications

• Benztropine is FDA-approved as an adjunctive therapy for all forms of parkinsonism, including idiopathic and postencephalitic parkinsonism.[2][3] 

• Benztropine is valuable in addressing drug-induced extrapyramidal symptoms, preventing dystonic reactions, and providing acute treatment for dystonic reactions.[4] The guidelines of the American Psychiatric Association (APA) support the use of anticholinergic medications, including benztropine, in the treatment of acute dystonia associated with antipsychotic therapy.[5]

Off-Label Uses

• Benztropine is used off-label for the treatment of chronic sialorrhea in developmentally disabled patients.[6] The medication demonstrated a substantial response in a small study, with 85% of patients showing improvement compared to only 15% in the placebo group.[7]

• Numerous clinical studies have been conducted on the use of benztropine in the management of intractable hiccups.[8]

Mechanism of Action

Benztropine antagonizes acetylcholine and histamine receptors. Benztropine exerts its action in the CNS and smooth muscles by competing with acetylcholine at muscarinic receptors. Consequently, it reduces central cholinergic effects by blocking muscarinic receptors, which appears to alleviate the symptoms of Parkinson disease.[9] 

In vivo, anticholinergic activity is about half as potent as atropine. Moreover, benztropine may prolong the action of dopamine by inhibiting its reuptake and storage. Data from animal studies suggest that the antihistamine effect of benztropine is similar to pyrilamine maleate.[10]

Pharmacokinetics

Absorption: The oral bioavailability of benztropine mesylate is low because of its limited gastric absorption and hepatic first-pass metabolism.

Distribution: Benztropine demonstrates high permeability across the blood-brain barrier, exerting a central anticholinergic effect.[11]

Metabolism: Benztropine has hepatic metabolism. In preclinical studies, administering benztropine (10 mg/kg body weight) to rats identified various metabolites in urine and bile. These metabolites include benztropine N-oxide, N-desmethylbenztropine, N-desmethyl-4'-hydroxybenztropine, 4'-hydroxybenztropine N-oxide, and methoxy-4'-hydroxybenztropine, along with the unchanged benztropine.[12]

Elimination: Metabolites of benztropine are excreted in urine and bile.[12]

Administration

Available Dosage Forms, Strengths, and Adult Dosage

Benztropine is administered through oral, intravenous (IV), and intramuscular (IM) routes. Each route has a particular advantage according to its specific indication.[13]

Oral Route: Benztropine mesylate is available in 0.5 mg, 1 mg, and 2 mg strengths for oral administration. The drug can be administered orally with no specific regard for meals. The oral route is preferable to address initial and acute symptoms of drug-induced Parkinsonism. Benztropine therapy may start with the lowest initial dose of 0.5 mg and may increase up to 6 mg for 5 to 6 days. Benztropine has cumulative action, so the dose should gradually be increased by 0.5 mg until optimal results are obtained without excessive adverse reactions.

IM route: Benztropine mesylate is available as a 1 mg/mL injection for IM administration. No significant clinical difference exists in the action of benztropine between IM or IV administration. IM administration of benztropine typically leads to complete resolution of acute dystonia within 20 to 30 minutes, and a repeat dose can be considered after 30 minutes if full recovery is not achieved.[14]

IV route: Benztropine mesylate is available as a 1 mg/mL injection for IV administration. The IV route should be reserved for drug-induced extrapyramidal symptoms or whenever oral and IM administration are unsuitable.

Specific Patient Populations

Hepatic impairment: The manufacturer label does not have information on benztropine in patients with hepatic impairment.

Renal impairment: The manufacturer label does not have information on benztropine in patients with renal impairment.

Breastfeeding considerations: According to current literature, the exact effects of benztropine on human breastfeeding are unknown. Furthermore, atropine, which shares structural similarities with benztropine, demonstrates little to no impact on human breastfeeding. However, some studies on antimuscarinic drugs, in general, have shown adverse effects on animal breastfeeding by reducing serum prolactin concentration in experimental animals. As a precautionary measure, it is advisable to contraindicate benztropine during breastfeeding.[15]

Pregnancy considerations: The effect of benztropine during pregnancy and labor is still unknown. Several cases in the literature discuss the impacts of benztropine administration during pregnancy. According to the literature, it is neither indicated nor contraindicated to use benztropine during pregnancy, as more clinical data and research are needed to detect the exact influence of benztropine.

Pediatric patients: Usually, pediatric patients are relatively more sensitive to anticholinergic agents. Therefore, benztropine is contraindicated in children younger than 3, infants, and neonates.

Older patients: Older patients are generally more sensitive to anticholinergic agents and respond relatively intensely to benztropine. The dose should be started at its lower end according to therapeutic needs. Additionally, oral benztropine is a potentially inappropriate medication in treating geriatric patients that have Parkinson disease according to the American Geriatrics Society Beers criteria. Thus, clinicians should avoid the usage of benztropine as a preventative agent for extrapyramidal disorders in geriatric patients. In general, the geriatric population should avoid potent anticholinergic agents such as benztropine because of the higher incidence of adverse effects among this group of patients. Common adverse effects of benztropine in geriatrics are delirium, confusion, drug-induced dementia, benign prostatic hyperplasia in males, and urinary tract problems.[16][17]

Adverse Effects

Adverse Effects

The adverse effects of benztropine range in severity from mild to moderate to severe.[18]

• Mild adverse effects of benztropine may include fever, rash, general weakness, lethargy, insomnia, nausea, vomiting, headache, drowsiness, paraesthesia, xerostomia, and mydriasis.

• Moderate adverse effects associated with benztropine may manifest as myasthenia, heatstroke, heat intolerance, or hyperthermia, visual hallucinations, delirium, confusion, toxic psychosis, depression, worsening of preexisting psychotic symptoms, blurred vision, cycloplegia, memory impairment, dry mouth, parotitis, dysuria, urinary tract infections, sinus tachycardia, constipation, and numbness of fingers.

• Severe adverse effects associated with benztropine may include toxic megacolon, ocular hypertension, paralytic ileus [19], and withdrawal of benztropine, leading to acute-onset dyskinesia.[20]

Drug-Drug Interactions

• The simultaneous administration of glucagon and anticholinergics, such as benztropine, is discouraged as it can lead to an escalation of gastrointestinal adverse reactions. This is attributed to the additive impact on inhibiting gastrointestinal motility.

• Concurrent administration of benztropine with antipsychotic medications, including high-potency first-generation antipsychotics, clozapine, or quetiapine, increases the risk of gastrointestinal hypomotility.[21]

• Paralytic ileus, hyperthermia, and heat stroke can occur if benztropine is combined with phenothiazines (first-generation typical antipsychotic medications), tricyclic antidepressants, and other anticholinergics. Use with caution.[22]

Contraindications

Boxed Warnings

Benztropine is contraindicated if the patient has a history of hypersensitivity to benztropine mesylate or any component of the drug formulation and children aged under 3.

Warning and Precautions

Urinary retention, bladder obstruction, and prostatic hypertrophy: Benztropine should be used cautiously for bladder obstruction and benign prostatic hypertrophy because it exerts anticholinergic effects. Also, benztropine may cause dysuria that can aggravate urinary tract problems, especially urine retention.[23]

Angle-closure glaucoma: Commonly, most anticholinergic drugs are avoided in closed-angle glaucoma. Benztropine is contraindicated in patients diagnosed with closed-angle glaucoma as it can cause mydriasis and cycloplegia. It can also lead to a significant increase in intraocular pressure indirectly.[24]

Tachycardia: Benztropine use requires extreme caution in cardiac patients, especially those with tachycardia, as it can worsen tachycardia due to its anticholinergic action at the sinoatrial (SA) node.[25]

Tardive dyskinesia: Long-term use of phenothiazines may cause the development of tardive dyskinesia. Although benztropine can be used to alleviate extrapyramidal symptoms, it is contraindicated for patients with tardive dyskinesia since benztropine and other anti-parkinsonian drugs can aggravate the symptoms of tardive dyskinesia instead of reducing them.[26]

Behavioral and psychological changes: Benztropine may impair mental and physical abilities. It can also cause vision impairment, including blurring effects that can be highly risky when performing potentially hazardous tasks such as operating machinery or driving. Using benztropine for treating extrapyramidal disorders in psychotic patients may exaggerate the psychotic symptoms and behavioral changes. Thus, it should be contraindicated for such cases since anti-parkinsonian drugs, including benztropine, can lead to toxic psychosis. Besides, benztropine can cause visual hallucinations and mental confusion at a relatively higher dosage. Also, the drug can intensify the symptoms of dementia, so it should be contraindicated in dementia patients.[27]

Myasthenia gravis and autonomic neuropathy: The anticholinergic effects of benztropine cause muscle weakness as it competes with acetylcholine at the neuromuscular junction. Thus, like other anticholinergic drugs, benztropine should be avoided in patients diagnosed with myasthenia gravis and autonomic neuropathy. If the patient starts to feel stiffness in the neck, followed by sudden relaxation, it indicates the need to adjust the benztropine dose.[28]

Alcoholism and hyperthermia: The similar structure and function between benztropine and atropine as anticholinergic agents can cause anhydrosis. The administration of benztropine in individual patients should be slow and under extreme caution. For instance, giving benztropine to patients with hyperthermia, alcoholism, who perform manual labor in a hot environment, and patients taking other atropine-like medications require extreme caution. Common signs of anhydrosis induced by benztropine are a disturbance in sweating and the development of hyperthermia.[29]

Contact lenses: Generally, anticholinergic drugs, including benztropine, usually cause eye dryness. Thus, patients who typically wear contact lenses may feel discomfort. Consequently, clinicians should advise patients to apply lubricant eye drops (artificial tears) before using contact lenses to relieve dryness. Patients should avoid contact lens use during benztropine treatment if the eye dryness is severe.

Monitoring

Monitoring the response to benztropine treatment and any unwanted anticholinergic effects is essential. For instance, patients with mental disorders can have a wide variety of reactions to benztropine treatment. Thus, they should be kept under close monitoring and observation, especially at the beginning of the treatment or when a dose increment is required in their cases to prevent any aggravation of neurological symptoms.[27]

Geriatric patients are more sensitive and have an intense response to anticholinergic medicines. Thus, the healthcare team should give extra attention to the dose and its effects on the patient's other pre-existing disorders. During benztropine use in geriatric patients, the dose should be started at the lower end because of higher sensitivity to the drug's adverse effects, like confusion and sedation.[16] Sufficient clinical monitoring is essential for benztropine administration in a relatively warm environment, as it can cause anhydrosis in specific groups of patients. In other words, the administration of benztropine should be careful in alcoholic patients and patients conducting manual labor in hot and humid weather. Therefore, meticulous supervision and monitoring are required.[30]

Toxicity

Signs and Symptoms of Overdose

Benztropine has been in use for over 50 years, and no reported incidents of liver injury exist due to the drug. The absence of liver injury is typical of anticholinergic agents and may also relate to the low therapeutic dose. However, benztropine overdose can cause an anticholinergic toxidrome, which, in its role, may require supportive care. The risk assessment for benztropine overdose can take place as soon as 6 hours after ingestion, and toxicity effects may vary between 12 hours and 5 days.[30] The most crucial step of proper detection of benztropine overdose involves conducting thorough investigations. It is recommended to obtain a 12-lead electrocardiogram (ECG). Monitoring the drug concentrations and blood glucose concentrations can become valuable for toxicity investigations if the toxicant is unknown. Patients who do not exhibit specific toxicity symptoms may need additional investigations, such as a lumbar puncture or brain CT scan.

Management of Overdose

Physostigmine is the antidote for benztropine toxicity in the event delirium is not controlled through benzodiazepines. It can be used for toxicity diagnosis if the patient regains a normal state after administration. However, caution should be practiced in determining its proper dose and route of administration since it can cause a cholinergic crisis that endangers the patient's life.[31] Decontaminating benztropine toxicity in cooperative and alert patients occurs by administering 50 g of activated charcoal during the first 2 hours of benztropine ingestion. Proper supportive care includes controlling delirium through IV administration of benzodiazepines such as diazepam. Also, catheter and bladder scans can help in case of urinary retention.[32]

Enhancing Healthcare Team Outcomes

The effective management of benztropine dosage and administration methods necessitates collaboration among interprofessional healthcare teams. The coordinated efforts of healthcare team members, including clinicians, neurologists, pharmacists, and nurses, can markedly enhance patient outcomes and contribute to successfully managing symptoms requiring benztropine therapy. 

Prescribers should start benztropine at a lower dosage and taper on gradually, especially in the geriatric population and patients with mental or behavioral issues. Neurologists should be consulted for advanced cases. Nurses should monitor patients for therapeutic success and any adverse events. When benztropine overdose is suspected, ICU nursing staff should monitor patients until the resolution of toxicity symptoms. The pharmacist can verify the appropriate dosing for the patient and review the patient's medication profile to find potential drug interactions. The ultimate objective is empowering healthcare professionals to deliver precise, patient-centered care, significantly improving management outcomes.