Biperiden

In rats the pharmacokinetic interactions between the anticholinergic drug biperiden and [3(H)]quinuclidinyl benzylate ([3(H)]QNB) or [3(H)]N-methylscopolamine ([3(H)]NMS) is affected by the sequence in which the drugs are administered. Drug concentrations in various tissues were determined after intravenous administration of [3(H)]QNB or [3(H)]NMS (325 ng kg(-1)). Biperiden (6.4 mg kg(-1)) was administered either 5 min before, concomitantly with or 20 min after injection of [3(H)]QNB or [3(H)]NMS. When biperiden was administered concomitantly with or before [3(H)]QNB, distribution of [3(H)]QNB among the regions of the brain and other tissues was reduced; at 4 hr the ratio of the distribution of [3(H)]QNB for experimental animals to that for control animals ranged from 0.15 to 0.9. When biperiden was administered after [3(H)]QNB, the distribution of [3H]QNB in the brain and other tissues was significantly higher than for the other two treatments (P < 0.01). However, for [3(H)]NMS the sequence of administration had no effect on the distribution of the drug in the brain and other tissues except for the kidney. In-vitro, in crude synaptosomal membranes, the amount of [3(H)]QNB at 2 hr relative to the control concentration at equilibrium was 87% when biperiden was added before [3(H)]QNB and 56% when biperiden was added after [3(H)]QNB. In both instances the concentration of [3(H)]NMS reached equilibrium within 30 min. These findings suggest that the difference between the rate constant of association and dissociation at the possible site of action gives rise to the effect of the sequence of administration on the pharmacokinetic interaction.

Concomitant administration of biperiden with other drugs having anticholinergic effects (e.g., opiate agonists, phenothiazines and other antipsychotics, tricyclic antidepressants, quinidine, antihistamines) may increase the risk of adverse anticholinergic effects.

In order to find molecules affected by administration of an antipsychotic drug with an antimuscarinic drug, which is a common prescription used to prevent extrapyramidal adverse effects caused by the antipsychotic drugs, gene expression profiling in the frontal cortex was studied in mice. After 14 days of administration with 2 mg/kg haloperidol, a typical antipsychotic drug, and 2 mg/kg biperiden, a high-affinity antagonist for muscarinic receptors in the brain, approximately 500 mRNAs related to synaptic function were investigated. The levels of the mRNAs related to the ubiquitin-related systems were significantly reduced after the combined administration. However, the separate administration of either haloperidol or biperiden had little effect on the levels of the mRNAs. This result suggests that coadministration of haloperidol and biperiden specifically affects the ubiquitin-related system.

Biperiden 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 biperiden liver injury in the literature and it must be a very rare cause of liver injury, if it occurs at all.

Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of action of centrally active anticholinergic drugs such as biperiden is considered to relate to competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance.

Signs of overdose include dilated and sluggish pupils, warm, dry skin, facial flushing, decreased secretions of the mouth, pharynx, nose, and bronchi, foul-smelling breath, elevated temperature, tachycardia, cardiac arrhythmias, decreased bowel sounds, urinary retention, delirium, disorientation, anxiety, hallucinations, illusions, confusion, incoherence, agitation, hyperactivity, ataxia, loss of memory, paranoia, combativeness, and seizures.

/SIGNS AND SYMPTOMS/ Overdosage with Akineton produces typical central symptoms of atropine intoxication (the central anticholinergic syndrome). Correct diagnosis depends upon recognition of the peripheral signs of parasympathetic blockade including dilated and sluggish pupils; warm, dry skin; facial flushing; decreased secretions of the mouth, pharynx, nose, and bronchi; foul-smelling breath; elevated temperature, tachycardia, cardiac arrhythmias, decreased bowel sounds, and urinary retention. Neuropsychiatric signs such as delirium, disorientation, anxiety, hallucinations, illusions, confusion, incoherence, agitation, hyperactivity, ataxia, loss of memory, paranoia, combativeness, and seizures may be present. The condition can progress to stupor, coma, paralysis, and cardiac and respiratory arrest and death.

/CASE REPORTS/ Two cases of self-induced intoxication with the anticholinergic agent biperiden (oral ingestion of at least 200 mg. in case 1, and of 60 mg. in combination with 300-400 mg levomepromazine in case 2) /were reported/. An acute delirious state and other somatic symptoms of a toxic anticholinergic action dominated the clinical picture. Serial measurements of biperiden serum levels revealed values up to 50-fold (case 1) and 15-fold (case 2) of those usually observed under therapeutic doses of biperiden. In both cases, the intoxication was controlled by the application of physostigmine and general therapeutic measures. ... The prognosis of biperiden intoxications, and the clinical symptomatology and therapy of drug-induced anticholinergic syndromes /is discussed/.

/CASE REPORTS/ Anticholinergic medication (ACM) is frequently used in psychiatry to treat the side-effects of D2 blocking agents. However, ACM is not without adverse effects and, in the elderly, cognitive and memory impairments have been emphasized. The aim of this study was to evaluate the effects of discontinuation of ACM on cognitive functions in a group of elderly chronic schizophrenia patients. Twenty-seven elderly patients (age 60 years or older), who were diagnosed as suffering from schizophrenia (DSM-IV) and receiving ACM in addition to antipsychotic treatment, were enrolled. Before and after ACM was discontinued, the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale was administered. Twenty-one patients completed the study. All were receiving Akineton (biperiden), 2-6 mg daily before the study. Significant improvement in the ADAS-Cog total score was demonstrated (P < 0.03), as well as in the ideational praxia and orientation subscales. Improvement was correlated with the previous dose of biperidin. No adverse events or emergent extrapyramidal symptoms were noted. Discontinuation of ACM may be warranted in chronic schizophrenia patients since it may improve cognitive functioning with no adverse effects.

/CASE REPORTS/ A case of contact dermatitis to biperiden, an anti-Parkinson agent, and photocontact dermatitis to phenothiazines in a pharmacist was reported. The patient developed eczematous lesions on exposed area after she had worked at a psychiatric hospital for 6 months. She showed positive patch test reaction to biperiden. In addition, she reacted positively to photopatch testing with ultraviolet A and phenothiazines such as chlorpromazine and perphenazine.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

biperiden

Akineton®

Anticholinergics

Not Applicable

no-DILI-concern

/LABORATORY ANIMALS: Acute Exposure/ In dogs under general anesthesia, respiratory arrest occurred at 33 mg/kg (intravenous) and circulatory standstill at 45 mg/kg (intravenous).

/LABORATORY ANIMALS: Acute Exposure/ Biperiden lactate (10 mg/mL) was not irritating to the tissue of rabbits when injected intramuscularly (1.0 mL) into the sacrospinalis muscles and intradermally (0.25 mL) and subcutaneously (0.5 mL) into the shaved abdominal skin. /Biperiden lactate/

/LABORATORY ANIMALS: Acute Exposure/ Biperiden lactate was administered intravenously in overdose to dogs under general anaesthesia. Biperiden appeared to have a toxic influence on respiration and circulation independently. Respiratory arrest occurred at a dose of 33 +/- 10 mg/kg and has probably a central origin. When artificial ventilation was instituted circulatory standstill occurred at a dose of 45 +/- 5 mg/kg. The toxic influence of biperiden is characterised by a decrease of heart rate and of left ventricular contractility resulting in cardiogenic shock. Biperiden is compared with orphenadrine as far as its potential hazard is concerned for patients trying to commit suicide by ingesting an overdose.

/LABORATORY ANIMALS: Neurotoxicity/ ... The anticholinergic drug, biperiden (40 mg/kg i.p.), /was administered/ to 10 adult male Wistar rats and ... the resulting polygraphic recordings, including electroencephalography (EEG), electrooculography (EOG), and electromyography (EMG), for 60 min following injection /was examined/. EEG data were investigated quantitatively by power spectrum analyses using fast Fourier transformation. Ten male Wistar rats receiving saline (i.p.) were used as the control group. Treated rats demonstrated two types of alternating behavioral change: a hyperactive and hypoactive state. In the hyperactive state, rapid walking, excessive random sniffing, and retropulsion were observed, with EEG desynchronization (significantly increased alpha1 (8.0-10.0 Hz), alpha2 (10.0-13.0 Hz), and beta (13.0-30.0 Hz) power values), as well as EEG slowing (significantly increased delta (0.5-4.0 Hz) and theta1 (4.0-6.0 Hz) power values): significantly marked rapid eye movement, and increased EMG activity. In the hypoactive state, motor arrest and drowsiness were observed, with prominent EEG slowing (significantly increased delta and theta1 power values): significantly decreased rapid eye movement and moderately decreased EMG activity. On the other hand, the control group did not show any behavioral or polygraphic changes.

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 BIPERIDEN (8 total), please visit the HSDB record page.

The metabolism of biperiden is not completely understood, but does involve hydroxylation.

The metabolism of biperiden is not completely understood, but does involve hydroxylation.

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BIPERIDEN

Established Pharmacologic Class [EPC] - Anticholinergic

Mechanisms of Action [MoA] - Cholinergic Antagonists

Biperiden is an Anticholinergic. The mechanism of action of biperiden is as a Cholinergic Antagonist.

Agents used in the treatment of Parkinson&apos;s disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting 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.

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.

87% bioavailability

The serum concentration at 1 to 1.5 hours following a single, 4 mg oral dose was 4-5 ng/mL. Plasma levels (0.1-0.2 ng/mL) could be determined up to 48 hours after dosing. Six hours after an oral dose of 250 mg/kg in rats, 87% of the drug had been absorbed.

The subcellular distribution of biperiden (BP), trihexyphenidyl (TP) and (-)-quinuclidinyl benzylate (QNB) in brain, heart and lung following high dose (3.2 mg/kg) iv administration was investigated in rats. The subcellular distribution of BP or TP used clinically conformed with that of QNB, a typical potent central muscarinic antagonist. The concentration-time courses of the brain subcellular fractions for these drugs were of two types which decreased slowly and in parallel to the plasma concentration. The subcellular distribution in the brain and heart was dependent on the protein amount of each fraction. The percent post-nuclear fraction (P2) of the total concentration in the lung was characteristically about 3-5 times larger than that in the heart. It was elucidated that the distribution in the lung differs from that in the brain and heart, with high affinity which is not dependent on the protein amount in the P2 fraction containing lysosomes. On the other hand, at a low dose (650 ng/kg) of 3H-QNB, each fraction as a percentage of the total concentration in the brain increased in synaptic membrane and synaptic vesicles and decreased in nuclei and cytosol as compared with the high dose. These results show that although the tissue concentration-time courses of anticholinergic drugs appear to decrease simply in parallel to plasma concentration, the subcellular distribution exhibits a variety of patterns among various tissues.

The pharmacokinetics of biperiden were studied and compared with pharmacodynamics (pupil size, accommodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 hr, biperiden was rapidly absorbed with a half-life of 0.3 hr, plasma peak levels of 5 ng/mL being reached after 1.5 hr. Biperiden showed good tissue penetration (distribution half-life 0.6 hr; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 hr, and the oral clearance was 146 L/hr. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 hr (accommodation).