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]

Benztropine antagonizes acetylcholine and histamine receptors. In the CNS and smooth muscles, benztropine exerts its action through competing with other cholinergic substances (especially acetylcholine) at muscarinic receptors. Consequently, it replaces cholinergic by muscarinic effects that appear to improve the symptoms of Parkinson disease. Besides, benztropine blocks the cholinergic muscarinic receptor in the central nervous system.[3] Thus, it reduces the cholinergic effects significantly during Parkinson disease. 

In vivo, anticholinergic activity is about half as active 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]

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 regards 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. 

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

Mild Side Effects:

• Fever
• Skin 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

Generally speaking, if the patient has a history of hypersensitivity to benztropine mesylate or any component of the 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 suffer from 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 parkinsonism 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 parkinsonism 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's 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 geriatric population should avoid potent anticholinergic agents such as benztropine thanks to the higher incidence of side effects among geriatric patients that may outweigh the benefits. Common side effects for 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 (lubricant 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 level 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.