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Buspirone
Brand name (BuSpar)
Pharmacology
Anxiolytic
Buspirone is a psychotropic drug with anxiolytic properties
which belongs chemically to the class of compounds known as
the azaspirodecanediones.
Buspirone shares some of the properties of the
benzodiazepines and the neuroleptics, as well as
demonstrating other pharmacological action. It attenuates
punishment suppressed behavior in animals and exerts a
taming effect, but is devoid of anticonvulsant and muscle
relaxant properties and does not bind to the
benzodiazepine/GABA receptor complex. Buspirone affects a
variety of dopamine mediated biochemical and behavioral
events, but is free of cataleptic activity. Buspirone has an
affinity for brain D(2)-dopamine receptors, where it acts as
an antagonist and agonist, and for the 5-HT(1A) receptors,
where it acts as an agonist. Buspirone does not block the
neuronal reuptake of monoamines and, on chronic
administration, it does not lead to changes in receptor
density in the models investigated. However, the mechanism
of action of buspirone remains to be fully elucidated.
Buspirone is rapidly absorbed in man and undergoes extensive
first pass metabolism. Following oral administration, low
peak plasma levels of unchanged drug, of 1 to 6 ng/mL were
observed 40 to 90 minutes after a single 20 mg dose. In a
number of studies performed in healthy volunteers, the mean
half-life of buspirone ranged from 2 to 3 hours up to
approximately 11 hours with considerable variation in
individual values. Multiple dose studies suggest that steady
state plasma levels were usually achieved within a few days.
Buspirone is metabolized primarily by oxidation, producing
several hydroxylated derivatives and a pharmacologically
active metabolite, 1-pyrimidinylpiperazine (1-PP). Peak
plasma levels of 1-PP have been found to be higher than
those of its parent drug and its half-life to be
approximately double that of unchanged buspirone. In a
single dose study using (14)C labeled buspirone, 29 to 63%
of the dose was excreted in the urine within 24 hours,
primarily as metabolites, while fecal excretion accounted
for 18 to 38% of the dose. In man, approximately 95% of
buspirone is plasma protein bound, but other highly bound
drugs, e.g. phenytoin, propranolol and warfarin, are not
displaced by buspirone from plasma protein in vitro.
However, in vitro binding studies show that buspirone does
displace digoxin.
The effect of food upon the bioavailability of buspirone was
studied in 8 subjects. The area under the plasma
concentration curve (AUC) and peak plasma concentration
(C(max)) of unchanged buspirone increased by 84% and 116%
respectively when the drug was administered with food, but
the total amount of buspirone immunoreactive material did
not change. The significance of this finding is not known,
but it could indicate that food may decrease the presystemic
clearance of buspirone.
Buspirone had no effect on hepatic microsomal enzyme
activity when administered to rats for 5 days. In man, the
effect of buspirone on drug metabolism or concomitant drug
disposition has not been studied. The pharmacokinetics of
buspirone in patients with hepatic or renal dysfunction, and
in the elderly, has also not been clearly established.
Indications
Short-term symptomatic relief of excessive anxiety in
patients with generalized anxiety disorder (psychoneurotic
disorder).
Eight 3-way short-term, controlled clinical trials involving
buspirone, diazepam and placebo are considered central to
the evaluation of buspirone as an anxiolytic agent. In 4 of
the 8 clinical trials, buspirone demonstrated a significant
difference from placebo. In the other 4 trials, there was no
significant difference between buspirone and placebo, but a
significantly greater improvement was observed in 2 of these
trials with diazepam than with placebo. The adverse effect
profiles of buspirone and diazepam in these clinical trials
were, however, different.
Contraindications
In patients hypersensitive to buspirone HCl.
Buspirone is contraindicated in patients with severe hepatic
or severe renal impairment.
Warnings
The occurrence of elevated blood pressure in patients
receiving both buspirone and a MAO inhibitor has been
reported. Therefore, it is recommended that buspirone should
not be used concomitantly with a MAO inhibitor.
Since buspirone can bind to central dopaminergic receptors,
the possibility of acute and chronic changes in dopamine
mediated neurological function (e.g. dystonia,
pseudo-parkinsonism, akathisia and tardive dyskinesia)
should be considered (see Precautions).
Since the effects of buspirone have not been evaluated in
patients with a history of convulsive disorders and since it
lacks anticonvulsant activity in animals, buspirone is not
recommended for patients with seizure disorders.
Use of Buspirone in Patients Previously Treated with a
Benzodiazepine:
Patients who have previously taken benzodiazepines may be
less likely to respond to buspirone than those who have not.
In 2 clinical studies to date, substitution of buspirone did
not ameliorate or prevent withdrawal symptoms in either
abrupt or gradual withdrawal from various benzodiazepines
following long-term use. Therefore, if it is considered
desirable to switch a patient who has been receiving
benzodiazepine therapy to buspirone, the benzodiazepine
should first be withdrawn gradually. A drug-free interval is
desirable between withdrawal of the benzodiazepine and
initiation of buspirone, in order to increase the likelihood
of distinguishing between benzodiazepine withdrawal effects
and unrelieved anxiety due to possible failure of buspirone
in this category of patients.
Benzodiazepine rebound or withdrawal symptoms may occur over
varying time periods depending in part on the type of drug
and its effective half-life of elimination. These symptoms
may appear as any combination of irritability, anxiety,
agitation, insomnia, tremor, abdominal cramps, muscle
cramps, vomiting, sweating, flu-like symptoms without fever
and, occasionally, seizures, and should be treated
symptomatically.
Pregnancy and Lactation:
The safety of buspirone during pregnancy and lactation has
not been established and, therefore, it should not be used
in women of childbearing potential or nursing mothers,
unless, in the opinion of the physician, the potential
benefits to the patient outweigh the possible hazards to the
fetus. Buspirone and its metabolites are excreted in milk in
rats. The extent of excretion in human milk has not yet been
determined.
Precautions
Effects on Cognitive and Motor Performance:
In controlled studies in healthy volunteers, single doses of
buspirone up to 20 mg had little effect on most tests of
cognitive and psychomotor function, although performance on
a vigilance task was impaired in a dose-related manner. The
effect of higher single doses of buspirone on psychomotor
performance has not been investigated.
Ten mg of buspirone given 3 times daily for 7 days to
healthy volunteers produced considerable subjective sedation
but no significant effect on psychomotor performance (no
vigilance tasks were used in this study). It also caused
transient dizziness, especially on standing and walking.
Occupational Hazards:
Until further experience is obtained with buspirone,
patients should be warned not to operate an automobile or
undertake activities requiring mental alertness, judgment
and physical coordination, until they are reasonably certain
that buspirone does not affect them adversely.
Significant Interactions:
In laboratory studies in healthy volunteers, buspirone in
doses up to 20 mg did not potentiate the psychomotor
impairment produced by relatively modest doses of alcohol.
However, decreased contentedness or dysphoria was observed
with a combination of alcohol and a 20 mg single dose of
buspirone. Since no data are available on concomitant use of
higher doses of buspirone and alcohol, it is prudent to
advise patients to avoid alcohol during buspirone therapy.
Food increased the bioavailability of unchanged buspirone in
healthy subjects, possibly due to a reduced first-pass
effect.
Concomitant use of MAO inhibitors and buspirone has been
reported to cause an increase in blood pressure. Therefore,
concomitant use of these medications is not recommended.
In a study in normal volunteers, no interaction of buspirone
with amitriptyline was seen. A similar study with buspirone
and diazepam showed an increase in the levels of nordiazepam.
In another study in normal volunteers, concomitant
administration of buspirone and haloperidol resulted in
increased serum haloperidol concentrations. The clinical
significance of this finding is not clear.
There is 1 report suggesting that the concomitant use of
trazodone and buspirone may have caused 3- to 6-fold
elevations in ALT (SGPT) in a few patients. In a similar
study, attempting to replicate this finding, no interactive
effect on hepatic transaminases was identified.
Because the effects of concomitant administration of
buspirone with most other psychotropic drugs have not been
studied, the concomitant use of buspirone with other CNS
active drugs should be approached with caution.
In vitro, buspirone does not displace tightly bound drugs
like phenytoin, propranolol and warfarin from serum
proteins. However, there has been 1 report of prolonged
prothrombin time when buspirone was added to the regimen of
a patient treated with warfarin. The patient was also
chronically receiving phenytoin, phenobarbital, digoxin and
Synthroid. In vitro, buspirone may displace less firmly
bound drugs like digoxin. The clinical significance of this
property is unknown.
There have been no reports to date of interference of
buspirone with commonly employed clinical laboratory tests.
Drug Abuse and Dependence:
Although preliminary animal and human investigations suggest
that buspirone may be significantly devoid of potential for
producing physical or psychological dependence, only
extensive clinical experience with the drug will provide
conclusive evidence. Meanwhile, physicians should carefully
evaluate patients for a history of drug abuse and follow
such patients closely, observing them for signs of buspirone
misuse and abuse.
Patients with Impaired Hepatic or Renal Function:
Since it is metabolized by the liver and excreted by the
kidneys, buspirone should be used with caution in patients
with a history of hepatic or renal impairment. It is
contraindicated in patients with severe hepatic or renal
impairment.
Children:
The safety and effectiveness of buspirone in individuals
below the age of 18 years have not been established.
Geriatrics:
Buspirone has not been systematically evaluated in older
patients. Although it would appear from limited
pharmacokinetic and clinical studies that buspirone does not
behave differently in the elderly, there is little known
about the effects of buspirone in this age group at doses
above 30 mg/day. Therefore, it is recommended that buspirone
should be used in the elderly at doses not exceeding 30
mg/day for a duration not exceeding 4 weeks.
Neuroendocrine Effects:
Single doses of 30 mg or higher of buspirone resulted in
significantly elevated plasma prolactin and growth hormone
concentrations in normal volunteers. No effect was seen at
lower doses. In another study, no such increases were
observed after buspirone was administered in divided doses
(10 mg t.i.d.) for 28 days.
Possible Concerns Related to Buspirone's Binding to Dopamine
Receptors:
Because buspirone can bind to central dopamine receptors, a
question has been raised about its potential to cause acute
and chronic changes in dopamine mediated neurological
function (e.g., dystonia, pseudoparkinsonism, akathisia, and
tardive dyskinesia). Clinical experience in controlled
trials has failed to identify any significant neuroleptic-like
activity; however, a syndrome of restlessness, appearing
shortly after initiation of treatment, has been reported in
some small fraction of buspirone treated patients. The
syndrome may be explained in several ways. For example,
buspirone may increase central noradrenergic activity;
alternatively, the effect may be attributable to
dopaminergic effects (i.e., represent akathisia). Obviously,
the question cannot be totally resolved at this point in
time. Generally, long-term sequelae of any drug's use can be
identified only after several years of marketing.
Adverse Effects
The most common adverse reactions encountered with buspirone
are dizziness, headache, drowsiness and nausea. During
premarketing clinical trials, approximately 10% of the
patients discontinued treatment due to an adverse event.
Adverse reactions reported include the following:
CNS:
Dizziness, headache, drowsiness, lightheadedness, insomnia,
fatigue, nervousness, decreased concentration, excitement,
depression, confusion, nightmares/vivid dreams,
anger/hostility. Infrequently (<1%) depersonalization, noise
intolerance, euphoria/feeling high, dissociative reaction,
fear, loss of interest, dysphoria, hallucinations, seizures,
suicidal thoughts. Rarely, slurred speech, claustrophobia,
cold intolerance, stupor, psychosis.
Neurologic:
Paresthesia, weakness, incoordination, tremor, numbness.
Infrequently, muscle cramps and spasms, rigid/stiff muscles,
involuntary movements, akathisia, slowed reaction time.
Rarely, tingling of limbs, stiff neck, rigidity of jaw,
ataxia.
Autonomic:
Dry mouth, sweating/clamminess, blurred vision,
constipation. Infrequently, urinary frequency, retention and
burning, flushing.
Cardiovascular:
Tachycardia, chest pain, palpitations. Infrequently,
syncope, hypotension, hypertension. Rarely, congestive heart
failure, cerebrovascular accident, myocardial infarction,
cardiomyopathy, bradycardia, EKG change.
Gastrointestinal:
Nausea, gastrointestinal distress, diarrhea, vomiting.
Infrequently, flatulence, increased appetite, anorexia,
hypersalivation, rectal bleeding, irritable colon. Rarely,
burning tongue.
Respiratory:
Nasal congestion. Infrequently, shortness of breath, chest
congestion, difficulty breathing, hyperventilation. Rarely,
epistaxis.
Endocrine:
Infrequently, decreased and increased libido, weight gain,
weight loss, menstrual irregularity/breakthrough bleeding.
Rarely, delayed ejaculation, impotence, galactorrhea,
amenorrhea, thyroid abnormality.
Allergic or Toxic:
Skin rash, sore throat. Infrequently, edema/facial edema,
pruritus, chills/fever. Rarely, photophobia, erythema,
flu-like symptoms.
Clinical Laboratory:
Infrequently, increases in liver enzymes. Rarely,
eosinophilia, leukopenia, thrombocytopenia.
Miscellaneous:
Tinnitus, muscle aches/pains. Infrequently, redness/itching
of eyes, altered taste/smell, roaring sensation in head,
malaise, easy bruising, dry skin, arthralgia, blisters, hair
loss. Rarely, acne, thinning of nails, sore eyes, inner ear
abnormality, pressure on eyes, nocturia, enuresis, hiccups,
voice loss, alcohol abuse.
Post Introduction Clinical Experience:
Post-marketing experience in the US has shown an adverse
experience profile similar to that given above. Additional
reports have included rare occurrences of allergic reaction,
cogwheel rigidity, dystonic reaction, ecchymosis, emotional
lability and tunnel vision. Because of the uncontrolled
nature of these spontaneous reports, a causal relationship
to buspirone treatment has not been determined.
Overdose
Symptoms:
In clinical pharmacology trials, buspirone up to 400 mg/day
was administered to healthy male volunteers. As this dose
was approached, the following symptoms were observed in
descending order of frequency: drowsiness, ataxia, nausea
and vomiting, dizziness, clammy feeling, difficulty
thinking, feeling high, rushing sensation, gastric distress,
headache, itching, miosis, hypotension, tremor,
incoordination, insomnia and hallucinations. In a dose
ranging study in acute psychotic patients, up to 2400 mg/day
was administered. Dizziness, nausea and vomiting were the
most common adverse effects. One patient developed
extrapyramidal symptoms at 600 mg/day.
Treatment:
There is no specific antidote for buspirone. Management
should, therefore, be symptomatic and supportive. Any
patient suspected of having taken an overdose should be
admitted to a hospital as soon as possible, and the stomach
emptied by gastric lavage. Respiration, pulse and blood
pressure should be monitored, as in all cases of drug
overdosage. As with the management of intentional overdosage
with any drug, the ingestion of multiple agents should be
suspected. In 6 anuric patients, hemodialysis either had no
effect on the pharmacokinetics of buspirone or decreased its
clearance.
Dosage
Dosage should be individually adjusted, according to
tolerance and response.
The recommended initial dose is 5 mg 2 to 3 times daily.
This may be titrated according to the needs of the patient
and the daily dose increased by 5 mg increments every 2 to 3
days up to a maximum of 45 mg daily in divided doses. The
usual therapeutic dose is 20 to 30 mg daily in 2 or 3
divided doses.
Geriatrics:
Limited pharmacokinetic and clinical data have shown no
difference in the effects of buspirone between elderly
patients and healthy adult volunteers. However, until more
information has accumulated in the elderly, it is
recommended that the maximum daily dose should not exceed 30
mg for a duration not exceeding 4 weeks.
Note:
If buspirone is administered to patients with compromised
hepatic or renal function, careful monitoring will be
required together with appropriate dosage adjustment.
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