AKINETON®
Knoll
Biperiden HCl
Anticholinergic – Antiparkinson Agent
Action And Clinical Pharmacology: Biperiden is an anticholinergic agent which acts primarily on the CNS. Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems. Accordingly, the mechanism of action of centrally active anticholinergic drugs, such as biperiden, is considered to relate to competitive antagonism of acetylcholine at the cholinergic receptors in the corpus striatum, which restores the balance. Similarly, biperiden has been shown to antagonize the Parkinson-like effects of agents with central cholinergic properties.
The peripheral anticholinergic effects of biperiden are small in comparison with atropine; giving rise to a lower incidence of antisecretory and mydriatic effects.
Biperiden binds competitively to peripheral and central muscarinic receptors. In vitro, it has a higher affinity for the M1 receptor compared to the M2 muscarinic receptor sub-type. Although the clinical significance of this selectivity has not been established, it may account for lower peripheral side effects in those tissues where M2 receptors predominate.
Pharmacokinetics: After oral administration of a single dose of 4 mg to young healthy subjects, absorption, after a mean lag time of 27 minutes to the appearance of detectable concentrations in the plasma, was rapid, a mean Cmax of 5.1 ng/mL being reached after 1.5 hours.
Systemic bioavailability is only 33±5%, due to intensive metabolism. The main metabolite is produced by hydroxylation at the bicyclus with some hydroxylation of the piperidine ring structure. No unchanged biperiden was found in the urine. Binding to plasma proteins was found to be 94% in women and 93% in men.
Indications And Clinical Uses: As an adjunct in the therapy of all forms of Parkinsonism (postencephalitic, arteriosclerotic, idiopathic), especially in cases where akinesia muscular rigidity and to a lesser extent tremor are the major presenting symptoms. Biperiden is also useful in the control of extrapyramidal disorders due to neuroleptic agents.
Parkinson’s Disease: In treating Parkinsonism, improvement of symptoms (primarily of rigidity) occasionally may occur as early as the second day at a dose of 1 to 2 mg 3 times daily. Usually, the maximum effect does not appear until after the first 3 to 4 days of treatment.
There are wide individual variations in the response of Parkinson’s disease to biperiden. Although excellent therapeutic results have been obtained, as well as satisfactory or moderate responses, the overall effect is at times inadequate. In view of this, the addition of drugs administered concomitantly is well accepted in the treatment of Parkinson’s disease. Nevertheless, it is advisable to start treatment with biperiden alone and not to institute additional therapy until is has been established that the effect of biperiden alone, at adequate dose, is unsatisfactory.
Drug-Induced Extrapyramidal Reactions: For drug-induced extrapyramidal reactions the effect of oral biperiden, depending on the nature and severity of the symptomatology, appears within a few hours to a few days. The duration of actions is dependent on the nature, severity and duration of extrapyramidal symptomatology, the type and dose of the psychotropic drug, the route of administration, whether and when administration of the psychoactive drug was discontinued, and on the dosage of biperiden.
Contra-Indications: Hypersensitivity to biperiden; untreated narrow angle glaucoma; stenosis in the gastrointestinal tract; megacolon.
Manufacturers’ Warnings In Clinical States: The use of biperiden is not recommended in patients with prostate adenoma, or with diseases which could lead to perilous tachycardia.
Isolated instances of mental confusion, euphoria, agitation and disturbed behavior have been reported following biperiden administration.
Precautions: Dependence Liability: Biperiden abuse has been observed, which may be related to a mood-lifting effect which has been occasionally observed.
Pregnancy: The safe use of biperiden in pregnancy has not been established and therefore it should not be used during pregnancy unless in the opinion of the prescribing physician the anticipated benefits outweigh the potential risks to the fetus.
Lactation: Although no data exists with regard to biperiden, anticholinergics in general may inhibit lactation. Biperiden has been found to pass into mother’s milk and can reach the same concentrations as those found in the mother’s plasma. Since the type and extent of metabolism in neonates are not known and since pharmacological and toxicological effects cannot be excluded, ablactation is generally recommended.
Children: Safety and effectiveness in children have not been adequately established.
Geriatrics: Elderly patients, particularly those with cerebral lesions of a vascular or degenerative nature, may exhibit increased sensitivity to biperiden (see Dosage).
Glaucoma: Caution should be observed in patients with manifest glaucoma, though no prohibitive rise in intraocular pressure has been noted following oral or parenteral administration of biperiden.
General: Patients with prostatism, epilepsy or cardiac arrhythmias should be given biperiden with caution.
Occupational Hazards: Occasionally drowsiness may occur following biperiden administration, and patients who drive a car or operate potentially dangerous machinery should be warned of this possibility.
As with other drugs affecting the CNS, the consumption of alcohol should be avoided during therapy with biperiden.
Side effects (see Adverse Effects) may occur in the early stages of treatment and particularly if the dose is increased too rapidly (see Dosage).
Except in the case of medical emergency, abrupt discontinuation of the drug is to be avoided, due to the risk of rebound imbalance between the cholinergic and dopaminergic regulatory systems.
The change from another antiparkinson drug to biperiden is best carried out gradually, i.e., biperiden is started at a low dose and gradually increased and the other drug is gradually decreased and discontinued. If L-Dopa is the other drug, it should be continued unless unacceptable toxicity occurs.
Drug Interactions: The central and peripheral side effects of biperiden may be potentiated when administered concomitantly with other anticholinergic drugs, or with drugs which have secondary anticholinergic activity, e.g. certain narcotic analgesics such as meperidine, the phenothiazines and other antipsychotics, tricyclic antidepressants, certain antiarrhythmics such as the quinidine salts, certain antihistamines and antispasmodics. The effect of metoclopramide is antagonized by biperiden.
The concurrent administration of biperiden with levodopa may potentiate dyskinesia. Tardive dyskinesia induced by neuroleptics may be intensified by biperiden. However, in cases where there is already tardive dyskinesia, occasionally the Parkinsonian symptoms may be so severe that continuation of biperiden therapy is justified.
Adverse Reactions: The common side effects which occur with biperiden administration in therapeutic doses, are dry mouth and blurred vision. These effects can be decreased or eliminated by reduction in oral dosage. Gastric irritation after oral biperiden may be avoided by administering the drug during or shortly after meals. A decrease in urinary flow has been noted in a few patients. Some patients may exhibit short periods of euphoria or disorientation.
In patients in the early stage of treatment in whom the dosage has been increased too rapidly, or in elderly patients with cerebral lesions of a vascular or degenerative nature, increased sensitivity to the recommended therapeutic doses may occur. In such cases, central side effects may take the form of fatigue, dizziness, euphoria or disorientation, at higher doses restlessness and confusion, occasionally impairment of memory and in rare cases, hallucinations. Peripheral side effects include dry mouth, blurred vision, hypohidrosis, constipation, urinary retention, and increase in heart rate, very rarely a decrease in heart rate.
Allergic skin rashes and dyskinesia have also been observed occasionally.
Symptoms And Treatment Of Overdose: Symptoms: Overdosage with biperiden produces both the central and peripheral symptoms typical of atropine toxicity.
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; urinary retention.
Neuropsychiatric signs such a 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, cardiac and respiratory arrest and death.
Treatment: Treatment of acute overdosage revolves around symptomatic and supportive therapy. Gastric lavage or other measures to limit absorption should be initiated. A small dose of diazepam or a short-acting barbiturate may be administered if CNS excitation is observed. Phenothiazines are contraindicated due to their antimuscarinic activity, which may intensify toxicity, causing coma.
Respiratory support, artificial respiration or the use of a vasopressor agent may be necessary. Hyperpyrexia must be reversed, fluid volume replaced and acid-base balance maintained. Urinary catheterization may be necessary.
The routine use of parenteral acetylcholine esterase inhibition, physostigmine is controversial. Delirium, hallucinations, coma and supraventricular tachycardia (but not ventricular tachycardia, nor conduction defects) seem to respond well to physostigmine 0.5 to 1.0 mg i.m. or by slow i.v. infusion. If there is no response within 20 minutes, an additional 1 mg dose may be given; this may be repeated until a total of 4 mg has been administered, a reversal of toxic effects is observed, or excessive cholinergic signs are seen. Frequent monitoring of clinical signs should be done. Since physostigmine is rapidly destroyed, additional injections may be required every 1 or 2 hours to maintain control. The relapse intervals tend to lengthen as the toxic anticholinergic agent is metabolized, so the patient should be carefully observed for 8 to 12 hours following the last relapse.
Dosage And Administration: General: Treatment with biperiden should be initiated with small doses, progressing gradually to optimum amounts. The dosage depending on the therapeutic effect and the side effects. The total daily oral dose should be distributed evenly throughout the day, and taken with or after food.
In older patients, especially those with cerebro-organic symptoms, conservative dosing is called for.
Experience with the use of biperiden in children is limited and arises mostly from short-term use in drug-induced dystonia (induced by neuroleptics, metoclopramide, or similar compounds).
Parkinson’s Disease: Treatment may be initiated with an oral dose of 1 mg twice daily. The dose can then be increased by 2 mg/day, up to a maximum of 16 mg/day. The average dose is 2 mg 3 to 4 times a day.
Drug-induced Extrapyramidal Reactions: The intensity of the extrapyramidal reaction, not the dosage of the drug inducing the reaction, is the decisive factor in determining the dosage of biperiden necessary for control. Size and weight of the patient and previous response to other antiparkinson drugs are also important in determining dosage.
A dose of 2 mg 1 to 3 times daily has proved to be of benefit for the prophylaxis and treatment of drug-induced extrapyramidal symptoms.
Availability And Storage: Each white, uncoated tablet, imprinted with the number 11 on one side and the Knoll triangle imprinted on the other side, contains: biperiden HCl USP 2 mg. Nonmedicinal ingredients: lactose anhydrous and magnesium stearate. Bottles of 100.
AKINETON® Knoll Biperiden HCl Anticholinergic – Antiparkinson Agent
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