Continuing Education Activity

Benztropine is FDA approved as adjunctive therapy for all forms of parkinsonism. It is also used for drug-induced extrapyramidal symptoms and the prevention of dystonic reactions as well as acute treatment of 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 this drug in patient care.

Objectives:

• Identify the mechanism of action of benztropine.
• Describe the adverse effects of benztropine.
• Review the appropriate monitoring and 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 drug). 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 effect compared to that of trihexyphenidyl, making it a preferable drug of choice for geriatric patients.[1] Moreover, benztropine is FDA approved as adjunctive therapy of all forms of parkinsonism, including:

• Idiopathic parkinsonism
• Postencephalitic parkinsonism

It is also useful for drug-induced extrapyramidal symptoms and the prevention of dystonic reactions and acute treatment of dystonic reactions. Furthermore, benztropine has further off-label use as it can treat chronic sialorrhea occurring in developmentally-disabled patients. Also, several clinical studies worked on using benztropine in managing intractable hiccups.[2]

Mechanism of Action

Benztropine antagonizes acetylcholine and histamine receptors. In the CNS and smooth muscles, benztropine exerts its action through 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. Thus, benztropine blocks the cholinergic muscarinic receptor in the central nervous system.[3] Therefore, it reduces the cholinergic effects significantly during Parkinson disease which becomes more pronounced in the nigrostriatal tract because of reduced dopamine concentrations. 

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.[4]

Administration

Benztropine administration routes include oral, intravenous, and intramuscular routes. Each route has a particular advantage according to its specific indication.[5]

Oral Route

Benztropine can be administered orally with no specific regard for meals. The oral route is preferable to address initial and acute symptoms of drug-induced parkinsonian symptoms. 

Intramuscular (IM) Route

There is no significant clinical difference in the action onset of benztropine between intramuscular or intravenous administration.

Intravenous (IV) Route

For drug-induced extrapyramidal symptoms, the IV route should be reserved for when oral and IM are not suitable. 

Adverse Effects

The adverse effects of benztropine range in severity from mild to moderate to severe [6].

Mild Side Effects

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

Moderate Side 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 Side Effects

• Toxic megacolon
• Paralytic ileus
• Ocular hypertension

Contraindications

Generally speaking, if the patient has a history of hypersensitivity to benztropine mesylate or any component of the drug formulation. Also, patients with specific syndromes and diseases are contraindicated from using benztropine as follows:

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 eliminate symptoms of these specific diseases. However, benztropine may cause dysuria that can aggravate urinary tract problems, especially urine retention.

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.[7]

Tachycardia

Benztropine use requires extreme caution in cardiac patients, especially those that present with tachycardia since it can cause tachycardia as a result of its anticholinergic action at the sinoatrial (SA) node. 

Tardive Dyskinesia

Long-term use of phenothiazines may cause the development of tardive dyskinesia. Although benztropine can be used to alleviate extrapyramidal disorders, it is contraindicated for patients with tardive dyskinesia since benztropine and other anti-parkinsonian drugs can severe the symptoms of tardive dyskinesia instead of reducing them.[8]

Behavioral and Psychological Changes

Benztropine may impair mental and physical abilities. It can also cause impairment of vision, 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 as well as mental confusion associated with higher patient susceptibility or relatively higher dosage. Also, it can intensify the symptoms of dementia, so it should be contraindicated in dementia patients.[9]

Effects on 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 given at its lower end at first before building that up 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 geriatric patients that may outweigh the benefits. Common side effects of benztropine in geriatrics are delirium, confusion, drug-induced dementia, benign prostatic hyperplasia in males, and urinary tract problems.[10]

Myasthenia Gravis and Autonomic Neuropathy

The anticholinergic effects of benztropine cause muscle weakness as it competes with acetylcholine at the neuromuscular junction (NMJ). Thus, benztropine, like other anticholinergic drugs, should be avoided in patients diagnosed with myasthenia gravis as well as autonomic neuropathy. If the patient starts to feel stiffness in the neck, followed by sudden relaxation, it is regarded as a sign indicating that the need to adjust the benztropine dose.[11]

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 chronic patients, and those with hyperthermia, alcoholism, who perform manual labor in a hot environment, and patients taking other atropine-like medications in relatively warm weather requires extreme caution. Common signs for anhydrosis induced by benztropine are a disturbance in sweating and the development of hyperthermia.[12]

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.

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. 

Breast-Feeding

There are not enough studies in the literature that define the exact effects of benztropine on human breastfeeding since 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, certain studies of antimuscarinic drugs, in general, proved that they harm animal breastfeeding since they reduced the concentration of serum prolactin in the experimental animals. Consequently, it is safe to contraindicate benztropine during breastfeeding as a cautionary measure.[13]

Pregnancy

The exact 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. Consequently, according to the literature, it is neither indicated nor contraindicated to use benztropine during pregnancy as more clinical data and research control trials are needed to detect the exact influence of benztropine.  

Monitoring

It is essential to monitor patients' response to benztropine treatment as well as any unwanted anticholinergic effects that can happen in specific cases of patients. For instance, patients with mental disorders can have a wide variety of responses to benztropine treatment. Thus, they should be kept under close monitoring and observation, especially at the beginning of the treatment course or even if a dosage increase is required in their cases to prevent any intensification of their mental symptoms. Moreover, geriatric patients are more sensitive and have a more intense response to anticholinergic treatment, especially to benztropine. Thus, supervised observation must be given extra attention to the dose and its effects on other pre-existing disorders that the patient has. During benztropine use in geriatric patients, the dose should be started at the lower end at first before building it up later because of higher sensitivity for the drug's side effects, e.g., confusion. 

Moreover, 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.[14]

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. Commonly, the risk assessment for benztropine overdose can take place as soon as 6 hours after overdose ingestion, and toxicity effects may last variably between 12 hours to 5 days at most.[14] 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 acetaminophen concentrations as well as blood glucose concentrations can become a useful method 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.

Decontamination of benztropine toxicity in cooperative and alert patients can be through the administration of 50 g of activated charcoal during the first 2 hours of benztropine ingestion. Proper supportive care in the case of benztropine toxicity is associated with the assessed symptoms resulted from toxicity. For instance, controlling delirium caused by its overdose is usually performed through IV administration of titrated doses of benzodiazepines such as diazepam. Also, catheter and bladder scans can help in case of urinary retention.[15]

Physostigmine is the usual antidote for benztropine toxicity in the event delirium is not controlled through benzodiazepines. Moreover, it can be used for toxicity diagnosis if the patient regains a normal state after administration. However, in both uses of physostigmine, 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.[16]

Enhancing Healthcare Team Outcomes

Management of benztropine dosage and methods of administration requires cooperation between different members of the interprofessional healthcare team. For instance, prescribing a proper dosage of benztropine to specific groups of patients, including the geriatric population, requires starting gradually from a low dose under special monitoring from healthcare team members, including nurses supervised by primary care practitioners. Also, proper control of patients with benztropine toxicity requires one on one nursing in ICU for symptomatic patients until the resolution of symptoms. The pharmacist can help in reviewing the patient's medication profile to determine potential drug interactions as well as recommend appropriate dosing for the patient. Cooperation of the healthcare team can greatly improve the healthcare outcomes for the patient. [Level V]