Brand Name: AKINETON®
Manufacturer: Knoll
Generic Name: Biperiden HCl
Drug Type: Anticholinergic - Antiparkinson Agent

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.

In comparative repeat dose studies (4 mg on day 1, followed by 2 mg b.i.d.
from day 8 to 14) in young healthy subjects, (19 to 28 years) and older
Parkinson patients (72 to 82 years), the following mean Cmax and Tmax were
found (see Table I).

Thereafter, the concentration curves exhibited an initially rapid, biphasic
decline (see Table II).

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:

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.

Contraindications:

Hypersensitivity to biperiden; untreated narrow angle glaucoma; stenosis in
the gastrointestinal tract; megacolon.

Warnings:

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 Effects:

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.

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:

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.

Supplied: 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. Bottles of 100.

Reviewed 1994

http://www.rxmed.com/monographs/akine.html



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613-256-8340   PO Box 171  Almonte  Ontario  K0A 1A0  Canada
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