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. Moreover, benztropine is FDA approved as adjunctive therapy of all forms of parkinsonism, including:
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.
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. 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.
Benztropine administration routes include oral, intravenous, and intramuscular routes. Each route has a particular advantage according to its specific indication.
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 .
Mild Side Effects:
Moderate Side Effects:
Severe Side Effects:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 at 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 Benztropine. Thus, supervised observation is a must giving extra attention to the dosage 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 on later on owing to their high sensitivity for the drug.
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 slow in chronic patients, alcoholic patients, and manual labor in a hot environment. Therefore, meticulous supervision and monitoring, in this case, is a vital need.
Benztropine has been in use for over 50 years, and there have been no report 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 in as soon as 6 hours after overdose administration, and toxicity effects may last variably between 12 hours to 5 days at most. 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 performing testing. Also, monitoring the paracetamol level as well as blood sugar level can become a useful method for toxicity investigations. 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 50g 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.
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 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.
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.
|||Benztropine 2012; [PubMed PMID: 31643727]|
|||Cunningham VL, Benztropine for the treatment of intractable hiccups: New indication for an old drug? CJEM. 2002 May; [PubMed PMID: 17609007]|
|||Guo MY,Etminan M,Procyshyn RM,Kim DD,Samii A,Kezouh A,Carleton BC, Association of Antidepressant Use With Drug-Related Extrapyramidal Symptoms: A Pharmacoepidemiological Study. Journal of clinical psychopharmacology. 2018 Aug; [PubMed PMID: 29901567]|
|||Chouinard G,Annable L,Ross-Chouinard A,Kropsky ML, Ethopropazine and benztropine in neuroleptic-induced parkinsonism. The Journal of clinical psychiatry. 1979 Mar; [PubMed PMID: 33969]|
|||Brocks DR, Anticholinergic drugs used in Parkinson's disease: An overlooked class of drugs from a pharmacokinetic perspective. Journal of pharmacy [PubMed PMID: 10952768]|
|||Siris SG,Rifkin A,Reardon GT,November M, Comparative side effects of imipramine, benztropine, or their combination in patients receiving fluphenazine decanoate. The American journal of psychiatry. 1983 Aug; [PubMed PMID: 6346910]|
|||Reid WH,Blouin P, Outpatient psychiatric medications and glaucoma. Psychosomatics. 1976; [PubMed PMID: 7801]|
|||Bergman H,Soares-Weiser K, Anticholinergic medication for antipsychotic-induced tardive dyskinesia. The Cochrane database of systematic reviews. 2018 Jan 17; [PubMed PMID: 29341071]|
|||Lupu AM,Clinebell K,Gannon JM,Ellison JC,Chengappa KNR, Reducing Anticholinergic Medication Burden in Patients With Psychotic or Bipolar Disorders. The Journal of clinical psychiatry. 2017 Nov/Dec; [PubMed PMID: 29178683]|
|||Friedman JH, Anticholinergics in dementia and other confounding problems. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2006 Apr; [PubMed PMID: 16582052]|
|||Howrie DL,Rowley AH,Krenzelok EP, Benztropine-induced acute dystonic reaction. Annals of emergency medicine. 1986 May; [PubMed PMID: 3963542]|
|||Stadnyk AN,Glezos JD, Drug-induced heat stroke. Canadian Medical Association journal. 1983 Apr 15; [PubMed PMID: 6831343]|
|||Benztropine 2006; [PubMed PMID: 30000721]|
|||McIntyre IM,Mallett P,Burton CG,Morhaime J, Acute benztropine intoxication and fatality. Journal of forensic sciences. 2014 Nov; [PubMed PMID: 24697166]|
|||Lynch MJ,Kotsos A, Fatal benztropine toxicity. Medicine, science, and the law. 2001 Apr; [PubMed PMID: 11368397]|
|||Thornton SL,Farnaes L,Minns A, Prolonged Antimuscarinic Delirium in a Child Due to Benztropine Exposure Treated With Multiple Doses of Physostigmine. Pediatric emergency care. 2016 Apr; [PubMed PMID: 26383155]|