TUGAS FARMASI RUMAH SAKIT

RINGKASAN JURNAL ALPRAZOLAM

Oleh:
MERI SANDI, S. Farm
( 1405011 )

Dosen: Hansen Nasif, SSi, Apt. SpFRS

PROGRAM PROFESI APOTEKER

SEKOLAH TINGGI FARMASI INDONESIA
YAYASAN PERINTIS
PADANG
2013

SUMMARY

Alprazolam, is a short-acting drug of the benzodiazepine, used to treat

moderate to severe anxiety disorders and panic attacks and is used as an adjunctive
treatment for anxiety associated with moderate depression. Alprazolam possesses
anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant properties.
Alprazolam may be habit-forming, and long-term use and abuse may cause a physical
dependence to develop along with withdrawal reactions during abrupt or rapid
discontinuation . Although the side-effect profile of alprazolam may occur in some
patients and are more likely the higher the dosage taken. Some side-effects may
disappear with continued treatment. If signs of an allergic reaction occur - such as
hives; difficulty breathing; swelling of face, lips, tongue, or throat.
Many research about alprazolam have been done. The research include; Effect
of Alprazolam (Xanax) on esophageal motility and acid reflux; UV
spectrophotometric Method for the estimation of Alprazolam in Tablet Dosag Form,
Adverse effect associated wwith the short- term treatment of panic disorder with
imipramine, alprazolam, or placebo; Differential metabolism of alprazolam by liver
and brain cytchrome (P4503A) to pharmacologically active metabolite; and
Alprazolam withdrawal and tolerance measured in the social conflict test in mice.
A method for the determination of Alprazolam in the bulk drug and tablet
formulations has been developed. The absorption spectrum of Alprazolam was
measured in the range of 200-400 nm against the blank solution 0.1N HCl similarly
prepared. The precision of the method was investigated with respect to repeatability

for intra-day precision, standard solution of fixed concentration was analyzed at

various time interval and % RSD was noted (limit %RSD<2.0%). And the day today
precision was studied by taking the absorbance of the same concentration of standard
solution at various days and the % RSD was calculated (%RSD<2.0). From the
spectrum of Alprazolam, it was found that the maximum absorbance is at about 260
nm in 0.1N HCl. A good linear relationship (0.997) was observed between the
concentration ranges of 1-70 gmL-1. The assay of Alprazolam was found to be
99.4%. The high percentage recovery indicates the high accuracy of the method. This
demonstrates that the develops Spectroscopic method is simple, accurate and
reproducible. Thus the developed method can be easily used for the routine quality
control of Alprazolam in tablet dosage form.
The research about Differential metabolism of alprazolam by liver and brain
cytchrome (P4503A) to pharmacologically active metabolite have been done.
Cytochrome P450 (P450) is a superfamily of enzymes which mediates metabolism of
xenobiotics including drugs. P450 mediated metabolism can lead to the detoxification
of drugs rendering them pharmacologically inactive, or on the other hand,
bioactivation can also take place wherein a drug can be metabolized to
pharmacologically active metabolite which may have longer or shorter half life
compared to parent drug. Metabolism may be necessary for pharmacological action,
if metabolite is active, and if metabolite is inactive, this would result in cessation of
drug action. Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver
by P4503A1 and P4503A4 respectively, to 4-hydroxy alprazolam (4-OHALP,
pharmacologically less active) and alprazolam (-OHALP, pharmacologically more

active). Examined P450 mediated metabolism of alprazolam by rat and human brain
microsomes and observed that the relative amount of -OHALP formed in brain was
higher than liver. This biotransformation was mediated by a P450 isoform belonging
to P4503A subfamily, which is constitutively expressed in neuronal cells in rat and
human brain. The formation of larger amounts of -OHALP in neurons points to local
modulation of pharmacological activity in brain, at the site of action of the antianxiety drug. Since hydroxy metabolites of alprazolam are hydrophilic and not easily
cleared through blood- CSF barrier, -OHALP would potentially have a longer halflife in brain.
The research about Adverse effect associated with the short- term treatment of
panic disorder with imipramine, alprazolam, or placebo have been done.. The safety,
side effects and patients' acceptance of alprazolam and imipramine versus placebo
were evaluated in 1168 subjects with panic disorder/agoraphobia who had been
enrolled in the second phase of the Upjohn World Wide Panic Study. Side effects that
worsened over baseline to a greater extent with alprazolam than with imipramine and
placebo were sedation, fatigue/weakness, memory problems, ataxia and slurred
speech. In the imipramine group blurred vision, tachycardia/palpitations, insomnia,
sleep disturbance, excitement/nervousness, malaise, dizziness/faintness, headache,
nausea/vomiting and decrease in appetite were worse than in the other groups. In the
placebo group the anxious symptoms were most prominent. The highest level of
compliance was shown in the alprazolam-treated group and the lowest in the placebotreated group. Strong predictors of side effects were not observed. If a side effect
profile is known, it will be easier for a clinician to choose the right drug and the

appropriate management by taking into account compliance, safety and efficacy in

each patient under treatment. Further information about side effects in long-term
maintenance treatment would be of great clinical pertinence in ensuring safety and
enhancing patients' quality of life.
Except of the adverse effect of alprazolam as generally, the other research
about Effect of Alprazolam (Xanax) on esophageal motility and acid reflux have been
done. The research aim to study the benefit and risk of anxiolity therapy on
esophegeal function. Because patients with spastics motor disorders have a high
frequency of psychiatric disordes, especially anxiety, depression, and panic attacks,
prompting some investigators to treat these patients with psychotropic drugs. Initial
theraupetic results have been encouraging, but the physological effect of central
nervous system depression ( a side effect of such therapy) on esophageal function is
not known.
Method of the study by using a randomized placebo controlled design in
healthy volounteers, the research following: - alprazolam had no significant effect on
esophageal smooth muscle function as assesed by its pressures or parameters of
esophagel peristaltis recorded during stationery or ambulatory monitoring;- In
contrast UES (Upper Esophageal Sphincter) pressure was sigificantly decreased
during alprazolam therapy. During the awake state, resting UES tone is generated by
constan neural discharges from the swallowing center of the striated muscle of the
sphincter Alprazolam probably decreased UES pressure by its depressive effects on
the central nervous system;- Finally and most important for treating patient with

esophageal diseases, one- third (3/9) of healthy volonteers had abnormal amount of
nocturnal acid reflux during the alprazolam phase of study.
Althuogh the study as small it learned that alprazolam significantly prolonged
the longest supine reflux episode. In addition, there was a strong tendency (p=0,06)
for the number of supine acid reflux episode > 5 min to increase. Together, these
changes confirm that alprazolam increased nocturnal esophageal acid exposure time
by impairing acid clearance. Gravity, esophageal motor activity , and saliva are
responsible for acid clearance during the day. Saliva flow is decreased and gravity
eliminated with sleep. This esophageal motor activityis the remaining nocturnal acid
clearance mechanism, but must be triggered by arousing the subject from sleep and
increasing the frequency of swallowing. Althuogh simultaneous EEGS were not
recorded, central nervous system depression by alprazolam probably interfered with
acid- induced arousal from sleep, thus impairing nocturnal acid clearance. This
hypothesis was supported by our finding that alprazolam significantly decrease the
number of esophageal contractions per minute in sleeping subject during ambulatory
pressure monitoring.
The research conclusion that alprazolam significantly increased esophageal
acid exposured time by interfering with the nocturnal clearance of refluxed acid.
Although not specifically studied, alprazolam probably supresses the arousal from
sleep induced by acid reflux. Therefore, alprazolam and other similiar acting
tranquilizers should be avoided in patient with esophageal diseases, particularly if
gastroesophageal reflux is present. These drug not only predispose reflux patient to
esophagitis, but may take then more prone to acid aspiration at night.

Benzodiazepines are widely used therapeutic agents with sedative, anxiolytic,

anticonvulsant and muscle relaxant effects in humans and animals. The use of these
agents is limited by the development of tolerance to their effects and the risk of
developing dependence. It is difficult to assess withdrawal from benzodiazepines, and
preclinical assessment of behavior during social conflict offers the opportunity to
quantify tolerance and withdrawal by measuring aggressive, defensive and social
behaviour. The relationship between benzodiazepine withdrawal symptoms and the
development of tolerance is not well understood. The aim of the research was to
compare the development of tolerance to alprazolam effects on the behavioural
repertoire during the social conflict test in mice, and to determine whether or not
behavioural changes during alprazolam withdrawal are correlated with the
development of tolerance. An experimental model consisting of interactions of pairs
of singly housed male mice with non-aggressive grouphoused male mice was used.
Alprazolam (1 mg/kg) was given orally once or repeatedly (twice daily) for 8 or 21
days. Behaviour was measured, based on videoanalysis, in aggressive mice before
treatment, 30 min or 3 days after the last dose, respectively. The result of the research
show that a single administration of alprazolam significantly reduced aggressive
activities and increased social investigation without changing locomotion or other
behaviour. Tolerance developed to the inhibitory effects of alprazolam on aggressive
behaviour but not to the effects of alprazolam to increase social investigation. When
withdrawn from alprazolam, mice exhibited less social investigation and locomotion
while aggression tended to be increased. Conclusion of the result show that tolerance
to the alprazolam effects on aggressive and social behaviour developed at different

rates suggesting that they are differentially regulated. Furthermore, the evidence of
withdrawal responses appearing in a behaviour to which tolerance had not developed
does suggest that tolerance and withdrawal phenomena are dissociated in
benzodiazepines.