Continuing Education Activity

Benztropine is FDA-approved as adjunctive therapy for all forms of parkinsonism. It is also used for drug-induced extrapyramidal symptoms, prevention of dystonic reactions, and treatment of acute dystonic reactions. This activity examines the indications, mechanism of action, dosing, adverse event profile, and other factors so members of the interprofessional healthcare team can make informed decisions regarding the use of benztropine.

Objectives:

• Identify the mechanism of action of benztropine.
• Describe the adverse effects of benztropine.
• Review the appropriate monitoring for toxicity of benztropine.
• Outline some interprofessional team strategies for improving care coordination and communication to advance the use of benztropine and improve outcomes.

Indications

Benztropine belongs to the synthetic class of muscarinic receptor antagonists (anticholinergic drugs). Thus, it has a structure similar to that of diphenhydramine and atropine. However, it is long-acting, so that its administration can be with less frequency than diphenhydramine. It also induces less CNS stimulation than trihexyphenidyl, making it a preferable drug of choice for geriatric patients.[1] 

• Benztropine is FDA approved as adjunctive therapy of all forms of parkinsonism, including:[2][3]
  • Idiopathic parkinsonism
  • Postencephalitic parkinsonism

• It is also useful for drug-induced extrapyramidal symptoms, the prevention of dystonic reactions, and acute treatment of dystonic reactions.[4]
• Furthermore, benztropine is used off-labeled as it can treat chronic sialorrhea occurring in developmentally-disabled patients.[5]
• Several clinical studies have been reported on using benztropine in managing intractable hiccups.[6]

Mechanism of Action

Benztropine antagonizes acetylcholine and histamine receptors. In the CNS and smooth muscles, benztropine exerts its action by competing with acetylcholine at muscarinic receptors. Consequently, it reduces central cholinergic effects by blocking muscarinic receptors that appear to improve the symptoms of Parkinson disease.[7] 

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. Animal data suggest that its antihistamine effect is similar to that of pyrilamine maleate.[8]

Administration

Benztropine is administered through oral, intravenous, and intramuscular routes. Each route has a particular advantage according to its specific indication.[9]

Oral Route

Benztropine mesylate is available as 0.5 mg, 1 mg, and 2 mg strengths for oral administration. It can be administered orally with no specific regard for meals. The oral route is preferable to address initial and acute symptoms of drug-induced Parkinson. Benztropine therapy may start with the lowest initial dose of 0.5 mg and may increase up to 6 mg over a period of 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.

Intramuscular (IM) Route

Benztropine mesylate is available as a 1 mg per mL injection for IM administration. There is no significant clinical difference in the action onset of benztropine between intramuscular or intravenous administration. 

Intravenous (IV) Route

Benztropine Mesylate is available as a 1 mg per 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 Population

Infants and Children

Usually, pediatric patients are relatively more sensitive to anticholinergic agents. Therefore, benztropine is contraindicated in children under the age of three years, infants, and neonates. 

Breastfeeding Women

There are not enough studies in the literature that define the exact effects of benztropine on human breastfeeding, so it is unknown whether it is excreted in human milk. Moreover, atropine (which is structurally similar to benztropine) has little to no effect on human breastfeeding as a general. However, in general, certain studies of antimuscarinic drugs proved that they harm animal breastfeeding since they reduced the serum prolactin concentration in the experimental animals. Consequently, it is safe to contraindicate benztropine during breastfeeding as a cautionary measure.[10]

Pregnancy

The effect of benztropine during pregnancy and labor is still unknown. There are several cases reported in the literature on 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.

Geriatric Population

Geriatric patients are generally more sensitive to anticholinergic agents and give a relatively intense response to benztropine. Thus, a higher dose of benztropine is contraindicated at the beginning of the treatment. The dose should be started at its lower end according to emerging therapeutic needs. Additionally, oral benztropine is a potentially inappropriate medication (PIM) in treating geriatric patients that have Parkinson disease according to Beers criteria. Thus, clinicians should avoid the usage of benztropine as a preventative agent for extrapyramidal disorders is avoided in geriatric patients. In general, the geriatric population should avoid potent anticholinergic agents such as benztropine because of the higher incidence of side effects among this group of patients. Common side effects of benztropine in geriatrics are delirium, confusion, drug-induced dementia, benign prostatic hyperplasia in males, and urinary tract problems.[11]

Hepatic or Renal Impairment

The manufacturer label does not have information on benztropine being used in this patient population.

Adverse Effects

The adverse effects of benztropine range in severity from mild to moderate to severe.[12]

Mild Adverse Effects

• Fever
• Rash
• General weakness, lethargy, and insomnia
• Nausea and vomiting
• Headache and drowsiness
• Insomnia
• Paraesthesia
• Xerostomia
• Mydriasis

Moderate Adverse Effects

• Myasthenia
• Heatstroke, heat intolerance, or hyperthermia
• Visual hallucinations and delirium
• Confusion and toxic psychosis
• Depression
• Psychotic symptoms (worsening of pre-existing symptoms)
• Blurred vision
• Cycloplegia
• Impairment of memory
• Dry mouth
• Parotitis
• Dysuria and urinary tract infections
• Sinus tachycardia
• Constipation
• Numbness of fingers

Severe Adverse Effects

• Toxic megacolon
• Paralytic ileus
• Ocular hypertension

Contraindications

Generally, benztropine is contraindicated if the patient has a history of hypersensitivity to benztropine mesylate or any component of the drug formulation. Also, benztropine is contraindicated in patients with the following specific syndromes and diseases:

Urinary Retention, Bladder Obstruction, and Prostatic Hypertrophy

Benztropine can be used with caution for bladder obstruction and benign prostatic hypertrophy because it exerts anticholinergic effects that can mask symptoms of these diseases. Also, benztropine may cause dysuria that can aggravate urinary tract problems, especially urine retention.[13]

Closed-Angle 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.[14]

Tachycardia

Benztropine use requires extreme caution in cardiac patients, especially those with tachycardia since it can worsen tachycardia due to its anticholinergic action at the sinoatrial(SA) node.[15]

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.[16]

Behavioral and Psychological Changes

Benztropine may impair mental and physical abilities. It can also cause vision impairment, including blurring effects that can cast a high risk 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, it can intensify the symptoms of dementia, so it should be contraindicated in dementia patients.[17]

Myasthenia Gravis and Autonomic Neuropathy

The anticholinergic effects of benztropine cause muscle weakness as it competes with acetylcholine at the neuromuscular junction(NMJ). 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.[18]

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 for anhydrosis induced by benztropine are a disturbance in sweating and the development of hyperthermia.[19]

Contact Lenses

In general, anticholinergic drugs, including benztropine, usually cause dryness in the eyes. Thus, patients that typically wear contact lenses may feel discomfort. Consequently, users of the medication should apply lubricant eye drops (artificial tears) before using contact lenses to relieve the dryness. If the eye dryness is severe, patients should avoid contact lens use during benztropine treatment.

Monitoring

• It is essential to monitor patients' response to benztropine treatment and any unwanted anticholinergic effects. 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 dose increment is required in their cases to prevent any intensification of their mental symptoms.[17]
• 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 other pre-existing disorders that the patient has. Therefore, during benztropine use in geriatric patients, the dose should be started at the lower end before building it up later because of higher sensitivity for the drug's side effects, e.g., confusion.[11]
• It is crucial to provide sufficient clinical monitoring for benztropine administration in a relatively warm environment as it can cause anhydrosis to 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, in this case, is a vital need.[20]

Toxicity

• Benztropine has been in use for over 50 years, and there have been no reported incidents of liver injury 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 to 5 days at most.[20] 
• The most crucial step of proper detection of benztropine overdose starts from carrying out intensive and inclusive investigations. For example, ECG can be an essential assessment tool using 12 leads during testing. Also, monitoring the medicine concentrations and blood glucose concentrations can become valuable for toxicity investigations if the toxicant is unknown. Undifferentiated patients that do not exhibit specific toxicity symptoms can have screening through many methods such as a lumbar puncture or brain CT scan.
• Decontaminating benztropine toxicity in cooperative and alert patients can be done 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.[21]
• 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 further.[22]

Enhancing Healthcare Team Outcomes

Management of benztropine dosage and methods of administration requires cooperation between different members of the interprofessional healthcare team. For instance, prescribers should be starting benztropine at a lower dosage and taper on gradually, especially in the geriatric population and patients with mental or behavioral issues. 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 appropriate dosing for the patient and review the patient's medication profile to find potential drug interactions. Collaborative work of the healthcare team members can significantly improve patient outcomes and lead to successful management of symptoms requiring benztropine therapy. [Level V]