Benztropine

307.4293

307.43

1NHL2J4X8K

DTXSID9022659

N - Nervous system

12.5

4.28 (est)

1.11g/cm3

138-140

409ºC at 760 mmHg

120.1ºC

1.604

H2O: Very soluble ;In water, 24.9 mg/L at 25 deg C (est)

Benztropine mesylate tablets should be stored in well-closed containers. Benztropine mesylate tablets and injection should be stored at a temperature less than 40 deg C, preferably between 15 - 30 deg C; freezing of the injection should be avoided.

6.86X10-7 mm Hg at 25 deg C (est)

Subcutaneous-mouse LD50: 60 mg/kg; intravenous-mouse LD50: 25 mg/kg

Flammable; burning produces toxic nitrogen oxide fumes

10None

Henry's Law constant = 2.23X10-9 atm-cu m/mol at 25 °C (est)

10

180.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Crystals from acetone+ether, mp 143 °C. UV max: 259 nm (Em = 437). Soluble in water. pH about 6 /Mesylate/|Hydroxyl radical reaction rate constant = 8.58X10-11 cu cm/molec-sec at 25 °C (est)

Ventilated, low temperature and dry; stored separately from food materials in warehouse

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl benztropine mesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Benztropine mesylate/

highly toxic

The oral LD50 of benztropine is reported to be of 940 mg/kg in rats.[MSDS] In the presence of overdose with benztropine, it has been observed symptoms of circulatory collapse, cardiac arrest, respiratory depression, respiratory arrest, psychosis, shock, coma, seizure, ataxia, combativeness, anhidrosis, hyperthermia, fever, dysphagia, decreased bowel sounds and sluggish pupils.

Benztropine has not been reported to cause serum aminotransferase elevations, but it has not been evaluated for effects on serum enzyme levels in a prospective manner. Despite its use for more than 50 years, there have been no reports of benztropine liver injury in the literature and it must be a very rare cause of liver injury, if it occurs at all. Absense of liver injury is typical of anticholinergic agents and may relate to the low doses used (less than 10 mg daily).

Concomitant administration of benztropine with other drugs having anticholinergic effects may increase the risk of adverse anticholinergic effects. Concomitant administration of an anticholinergic antiparkinsonian agent (e.g., benztropine) with phenothiazines and/or tricyclic antidepressants may cause paralytic ileus, hyperthermia, or heat intolerance, effects that occasionally have been fatal. Patients who are receiving benztropine concomitantly with phenothiazines, haloperidol, or other drugs with anticholinergic or antidopaminergic activity should notify their clinicians promptly if adverse GI effects, fever, or heat intolerance occurs.|On the basis of recent findings, the increased use of serotonin selective reuptake inhibitors (SSRIs) in combination with antipsychotics and concomitant benztropine is likely. Five patients who developed delirium while receiving a neuroleptic, an SSRI, and benztropine are described. The timing of the delirium in relation to drug administration suggests the delirium was the result of an interaction of the SSRI and benztropine. Possible mechanisms are explored. Clinicians should be aware that patients receiving this combination may be at increased risk for delirium.|Patients receiving benztropine concomitantly with phenothiazines or other drugs with anticholinergic effects should be warned to promptly report any adverse GI effects, since paralytic ileus, sometimes fatal, has occurred during concomitant therapy with these drugs.

Six cases of toxic psychosis occurring in drug abusers prescribed benztropine are reported. Five patients were heroin (diacetylmorphine) addicts for whom haloperidol was used as an aid in withdrawal. The other patient was a schizophrenic who abused hallucinogenic drugs and was being treated with fluphenazine enanthate and benztropine. One patient became psychotic after taking a substantial overdose of benztropine in an attempt to get "high"; 2 became psychotic after taking doses of benztropine that were within the accepted therapeutic range; 3 became psychotic after self-medication with more than the prescribed dose of benztropine. The cases serve to illustrate the problems encountered in prescribing anticholinergic drugs to drug abusers. They also suggest that heroin addicts may be unusually sensitive to the toxic psychotic effects of anticholinergic medication.|Since benztropine has cumulative effects, continuous supervision of patients receiving the drug is advised, especially for those with a tendency toward tachycardia, or with prostatic hypertrophy. Patients with mental disorders receiving benztropine for control of drug-induced extrapyramidal effects should also be carefully observed, especially at the beginning of therapy or during dosage adjustment, since worsening of mental symptoms or toxic psychosis can occur.|Benztropine is contraindicated in children younger than 3 years of age and should be used with caution in older children because of the drug's adverse anticholinergic effects.

About 95% of the administered dose of benztropine is found bound to plasma proteins.

Benztropine's production of Cogentin (benztropine mesylate, used in the treatment of all forms of parkinsonism)(1), may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1X10+5(SRC), determined from a structure estimation method(2), indicates that benztropine is expected to be immobile in soil(SRC). Volatilization of benztropine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.2X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Benztropine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-7 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2008).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1X10+5(SRC), determined from a structure estimation method(2), indicates that benztropine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.2X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 400(SRC), from an estimated log Kow of 4.3(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Biodegradation data were not available(SRC, 2008).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), benztropine, which has an estimated vapor pressure of 6.9X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase benztropine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5 hrs(SRC), calculated from its rate constant of 8.6X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase benztropine may be removed from the air by wet or dry deposition(SRC). Benztropine does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of benztropine with photochemically-produced hydroxyl radicals has been estimated as 8.6X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Benztropine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Benztropine does not contain chromophores that absorb at wavelengths >290 nm(2) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 400 was calculated in fish for benztropine(SRC), using an estimated log Kow of 4.3(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of benztropine can be estimated to be 1X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that benztropine is expected to be immobile in soil.

The Henry's Law constant for benztropine is estimated as 2.2X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that benztropine is expected to be essentially nonvolatile from water surfaces(2). Benztropine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-7 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to benztropine were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).

NIOSH (NOES Survey 1981-1983) has statistically estimated that 103 workers (52 of these were female) were potentially exposed to benztropine in the US(1). Occupational exposure to benztropine may occur through inhalation and dermal contact with this compound at workplaces where benztropine is produced or used(SRC). Exposure to benztropine among the general population may be limited to those administered the drug Congentin(SRC).

Benztropine is indicated to be used as an adjunct in the therapy of all forms of parkinsonism. It can also be used for the control of extrapyramidal disorders due to neuroleptic drugs. The extrapyramidal symptoms are defined as drug-induced disorders that include symptoms of dystonia, akathisia, parkinsonism, bradykinesia, tremors, and dyskinesia. Parkinsonism is a general term that refers to the group of neurological disorders that produce symptoms similar to Parkinson's disease such as tremors, slow movement, and stiffness. The parkinsonism includes a large number of disorders and some of them have not been clearly defined.|FDA Label

Benztropine is an anticholinergic agent used predominantly in the symptomatic therapy of Parkinson disease and movement disorders. Benztropine has not been associated with serum enzyme elevations during treatment and has not been linked to cases of clinically apparent acute liver injury.

Antiparkinson Agents

Antiparkinson Agents; Dopamine Uptake Inhibitors; Muscarinic Antagonists; Parasympatholytics|Benztropine mesylate is used for the adjunctive treatment of all forms of parkinsonian syndrome including the postencephalitic, idiopathic, and arteriosclerotic types. Benztropine is also used for the relief of parkinsonian signs and symptoms of antipsychotic agent-induced (e.g., phenothiazines) extrapyramidal reactions except tardive dyskinesia. Benztropine may be used alone or in conjunction with other antiparkinsonian drugs. Geriatric patients who do not tolerate cerebral-stimulating agents may respond to benztropine.

Since benztropine has cumulative effects, continuous supervision of patients receiving the drug is advised, especially for those with a tendency toward tachycardia, or with prostatic hypertrophy. Patients with mental disorders receiving benztropine for control of drug-induced extrapyramidal effects should also be carefully observed, especially at the beginning of therapy or during dosage adjustment, since worsening of mental symptoms or toxic psychosis can occur.|Benztropine should be used with caution or may be contraindicated in patients with conditions in which anticholinergic effects are undesirable. The usual precautions and contraindications associated with antimuscarinics should be observed with benztropine.|Adverse reactions to benztropine are mainly extensions of its anticholinergic and antihistaminic effects. Dryness of the mouth, blurred vision, mydriasis, nausea, nervousness, tachycardia, or skin rash may occur. In high dosage or in particularly susceptible patients, mental confusion and excitement, weakness and inability to move certain muscle groups, and, occasionally, urinary retention and/or difficulty in urination may result. Constipation, numbness of the extremities, listlessness, depression, vomiting, paralytic ileus, hyperthermia, fever, heat stroke, and visual hallucinations have also been reported. Adjustment of dosage will usually overcome most adverse effects of benztropine, but in the event of severe reactions, such as excitement or vomiting, the drug should be withdrawn and later resumed at a lower dosage.|Dosage of benztropine mesylate should be individualized according to the age and weight of the patient and the type of parkinsonian syndrome being treated. Geriatric patients or those with less than average body weight generally cannot tolerate high dosages of the drug.|For more Drug Warnings (Complete) data for BENZTROPINE (16 total), please visit the HSDB record page.

The inhibition of dopamine reuptake by benztropine produces a dose-dependent increase of dopamine in the nerve terminal of the dopaminergic system. Clinically the activity of benztropine is observed after 1-2 hours of oral administration and after a few minutes of intramuscular administration with a last-longing effect of about 24 hours. Reports have indicated that benztropine has a very large sedative effect. The antihistaminic effect of benztropine is very similar to the effect found in [pyrilamine] and the anticholinergic activity was found to be equal to [atropine] _ex vivo_ and of about 50% activity _in vivo_.

Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists. (See all compounds classified as Antiparkinson Agents.)|Drugs that block the transport of DOPAMINE into axon terminals or into storage vesicles within terminals. Most of the ADRENERGIC UPTAKE INHIBITORS also inhibit dopamine uptake. (See all compounds classified as Dopamine Uptake Inhibitors.)|Drugs that bind to but do not activate MUSCARINIC RECEPTORS, thereby blocking the actions of endogenous ACETYLCHOLINE or exogenous agonists. Muscarinic antagonists have widespread effects including actions on the iris and ciliary muscle of the eye, the heart and blood vessels, secretions of the respiratory tract, GI system, and salivary glands, GI motility, urinary bladder tone, and the central nervous system. (See all compounds classified as Muscarinic Antagonists.)|Agents that inhibit the actions of the parasympathetic nervous system. The major group of drugs used therapeutically for this purpose is the MUSCARINIC ANTAGONISTS. (See all compounds classified as Parasympatholytics.)

Oral administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%.|Benztropine is mainly excreted in the urine but it is also found in the feces unchanged.|Benztropine is expected to present a large volume of distribution between 12-30 L/kg.|Extensive pharmacodynamic or pharmacokinetic studies have not been performed.

Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates.|Following oral administration of benztropine (10 mg/kg, body weight), the phase I metabolites, benztropine N-oxide, N-desmethylbenztropine, tropine, 4'-hydroxybenz- tropine, N-desmethyl-4'-hydroxybenztropine, 4'-hydroxvbenztropine N-oxide and methoxy-4'-hydroxybenztropine, together with unmetabolized benztropine, were isolated and identified in rat urine and bile by GC-electron impact mass spectrometry (EI GC/MS), microcolumn LC-electrospray mass spectrometry (ES LC/MS) and HPLC followed by MS analysis. The mass spectra and chromatographic properties of isolated N-desmethylbenztropine, benztropine N-oxide and tropine were confirmed by comparison with authentic reference standards. Sufficient quantities of 4'-hydroxybenztropine and N-desmethyl-4'-hydroxybenztropine were isolated from the urine by tlc and examined by 1H-nmr, ES/MS and EI/MS. The structure of the methoxy-4'-hydroxybenztropine metabolite was determined by EI/MS. 4'-Hydroxybenztropine N-oxide was identified by reacting it with a reducing agent, titanous chloride, to form 4'-hydroxybenztropine, which was then confirmed by comparing its EI/MS and ES/MS behaviour with a previously isolated and 1H-nmr-authenticated sample. In addition, four intact glucuronide conjugates of benztropine were also characterized in bile and urine as phase II metabolites, including 4'-O-glucuronylbenzotropine, N-desmethyl-4'-O-glucuronylbenztropine, methoxy-4'-O-glucuronylbenztropine and 4'- O-glucuronylbenztropine N-oxide by hplc followed by ES/MS analysis. These results provide the first direct evidence of the presence of these metabolites of benztropine in rat.

The elimination half-life of benztropine is very variable and it is reported to be of around 36 hours.

Benztropine is an agent with anti-muscarinic and antihistaminic effects. Its main mechanism of action is presented by the selective inhibition of dopamine transporters but it also presents affinity for histamine and muscarine receptors. It is widely known that benztropine is a potent inhibitor of presynaptic carrier-mediated dopamine transport. As well, it is known to be an analog of atropine and hence, it has a large affinity for muscarinic receptors M1 in the human brain. Once bound, benztropine blocks the activity of the muscarinic receptors mainly in the striatum. The increased advantage of benztropine lays on the antagonism of acetylcholine activity which corrects the imbalance between dopamine and acetylcholine in Parkinson patients.|/Benztropine mesylate/ possess both anticholinergic and antihistaminic effects, although only the former have been established as therapeutically significant in the management of parkinsonism. /Benztropine mesylate/|Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very different psychostimulant effects when compared with another inhibitor, cocaine. Taking advantage of the differential sensitivity of the dopamine and the norepinephrine transporters (DAT and NET) to benztropine and bupropion, we have used site-directed mutagenesis to produce gain-of-function mutants in NET which demonstrate that Ala279 in the trans-membrane domain 5 (TM5) and Ser359 in the TM7 of DAT are responsible for the higher sensitivity of DAT to both bupropion and benztropine. Substitution of these two DAT residues into the NET background does not alter the potency of NET-selective inhibitors, such as desipramine. The results from experiments examining the ability of DAT-selective inhibitors to displace [3H]nisoxetine binding in NET gain-of-function mutants suggest that Ser359 contributes to the initial binding of the inhibitor, and that Ala279 may influence subsequent steps involved in the blockade of translocation. Thus, these studies begin to identify residues that are important for the unique molecular interactions of benztropine and bupropion with the DAT, and that ultimately may contribute to the distinct behavioral actions of these drugs.

Emergency and supportive measures: Maintain an open airway and assist ventilation if needed. Treat hyperthermia, coma, rhabdomyolysis, and seizures if they occur. /Anticholinergics/|Specific drugs and antidotes: A small dose of physostigmine .... can be given to patients with severe toxicity (e.g., hyperthermia, severe delirium, or tachycardia). Caution: Physostigmine can cause AV block, asystole, and seizures, especially in patients with tricyclic antidepressant overdose. Neostigmine, a peripherally acting cholinesterase inhibitor, may be useful in treating anticholinergic-induced ileus. /Anticholinergics/|Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of slowed gastrointestinal motility, gut decontamination procedures may be helpful even in late-presenting patients. /Anticholinergics/|Enhanced elimination: Hemodialysis, hemoperfusion, peritoneal dialysis, and repeat-dose charcoal are not effective in removing anticholinergic agents. /Anticholinergics/|For more Antidote and Emergency Treatment (Complete) data for BENZTROPINE (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ May be any of those seen in atropine poisoning or antihistamine overdosage: CNS depression, preceded or followed by stimulation; confusion; nervousness; listlessness; intensification of mental symptoms or toxic psychosis in patients with mental illness being treated with neuroleptic drugs (e.g., phenothiazines); hallucinations (especially visual); dizziness; muscle weakness; ataxia; dry mouth; mydriasis; blurred vision; palpitations; tachycardia; elevated blood pressure; nausea; vomiting; dysuria; numbness of fingers; dysphagia; allergic reactions, e.g., skin rash; headache; hot, dry, flushed skin; delirium; coma; shock; convulsions; respiratory arrest; anhidrosis; hyperthermia; glaucoma; constipation.|/CASE REPORTS/ A case of benztropine-induced acute dystonia and dyskinesia without findings of acute anticholinergic toxicity in a 20-month-old child /was reported/. Laboratory analysis of blood, urine, and gastric contents demonstrated the presence of an atropinic compound and diphenhydramine only, suggesting the association of benztropine and acute dystonia. Effects of benztropine on neuronal uptake of dopamine may represent a possible mechanism for this unusual adverse effect.|/CASE REPORTS/ A 38-year-old man overdosed on benztropine mesylate and developed anticholinergic poisoning syndrome, which lasted nine days. Serial serum benztropine concentrations were obtained during his hospitalization. Fluctuating benztropine levels suggested that his lengthy intoxication may have been secondary to prolonged, intermittent absorption rather than from slow plasma clearance. ...|/CASE REPORTS/ Six cases of toxic psychosis occurring in drug abusers prescribed benztropine are reported. Five patients were heroin (diacetylmorphine) addicts for whom haloperidol was used as an aid in withdrawal. The other patient was a schizophrenic who abused hallucinogenic drugs and was being treated with fluphenazine enanthate and benztropine. One patient became psychotic after taking a substantial overdose of benztropine in an attempt to get "high"; 2 became psychotic after taking doses of benztropine that were within the accepted therapeutic range; 3 became psychotic after self-medication with more than the prescribed dose of benztropine. The cases serve to illustrate the problems encountered in prescribing anticholinergic drugs to drug abusers. They also suggest that heroin addicts may be unusually sensitive to the toxic psychotic effects of anticholinergic medication.|For more Human Toxicity Excerpts (Complete) data for BENZTROPINE (9 total), please visit the HSDB record page.

Apo Benztropine

Trade Names. Cogentin (Merck, Sharp & Dohme), Cogentinol (Astra). /Benztropine mesylate/|Parenteral: Injection: 1 mg/mL Cogentin (with sodium chloride 9 mg/mL) (Ovation). /Benztropine mesylate/|Oral: Tablets: 0.5 mg Benztropine Mesylate Tablets (Corepharma, Par, Pliva, Rising Pharmaceuticals, Upsher-Smith); 1 mg Benztropine Mesylate Tablets (Corepharma, Par, Pliva, Rising Pharmaceuticals, Upsher-Smith); 2 mg Benztropine Mesylate Tablets(Corepharma, Par, Pliva, Rising Pharmaceuticals, Upsher-Smith). /Benztropine mesylate/

BENZTROPINE IS BENZHYDRYL ESTER OF TROPINE.

Method: AOAC 973.75; Procedure: spectrophotometric method; Analyte: benztropine mesylate; Matrix: drugs; Detection Limit: not provided. /Benztropine mesylate/|Analyte: benztropine mesylate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /benztropine mesylate/|Analyte: benztropine mesylate; matrix: chemical purity; procedure: dissolution in water; addition of sodium carbonate; extraction with chloroform; addition of methyl red indicator; titration with perchloric acid in dioxane with comparison to standards /benztropine mesylate/|Analyte: benztropine mesylate; matrix: pharmaceutical preparation (injection solution; tablet); procedure: thin-layer chromatography with comparison to standards (chemical identification) /benztropine mesylate/|For more Analytic Laboratory Methods (Complete) data for BENZTROPINE (7 total), please visit the HSDB record page.

Analyte: benztropine mesylate; matrix: blood (plasma, whole); procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm; limit of detection: 10 ng/mL /benztropine mesylate/|Analyte: benztropine mesylate; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 199 nm; limit of quantitation: 0.25 ng/mL /benztropine mesylate/|Analyte: benztropine mesylate; matrix: blood (serum), tissue (liver); procedure: high-performance liquid chromatography with ultraviolet detection at 220 nm /benztropine mesylate/

Pharmaceuticals