Drug Profile of ALPRAZOLAM

Submitted by
Roll NO. 55-E-16

Name: Muhammad Shahzad Asif

Session: 2016-2021

Submitted T0
Dr. Abdul Majeed
Subject:
Clinical Pharmacy

FACULTY OF PHARMACY

BAHAUDDIN ZAKARIYA UNIVERSITY MULTAN

PAKISTAN
 ALPRAZOLAM

Alprazolam is used to treat anxiety and panic disorders. It belongs to a class of medications
called benzodiazepines which act on the brain and nerves (central nervous system) to produce a
calming effect. It works by enhancing the effects of a certain natural chemical in the body
(GABA).

1.PRODUCTS DISCRIPTION:
Alprazolam is available in following brands in Pakistan.

Tablets:

 0.25mg
 0.5mg
 1mg
 2mg

Brand Manufacture Representative Dosage Form Price 0.5mg

Name Packing:30s
Alp Hilton Pharma(Pvt) Ltd Tabs 152.99
Alpax Efroz Chemical Industries Tabs 160
Xanax Pfizer Laboratories Ltd Tabs 219.82
Pranax Aries Pharma (Pvt) Ltd Tabs 158
Praz Getz Pharma Pakistan Tabs 128
Neram Genix Pharma (Pvt) Lltd Tabs 148
Bizolam Bio Labs (Pvt) Ltd Tabs 152

2.CHEMISTRY OF ALPRAZOLAM:
Structure:
IUPAC Name: 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine

Molecular formula: C17H3ClN4

Properties:
Physical Description: Solid
Color/Form: Crystals from ethyl acetate
Melting Point: 228-229.5 °C
Solubility:
In water, 13.1 mg/L at 25 °C (est)
Insoluble in water
Freely soluble in chloroform, soluble in alcohol; sparingly soluble in acetone; solubility
soluble in ethyl acetate
STORAGE :Store at room temperature away from light and moisture. Do not store in the
bathroom. Keep all medications away from children and pets.Do not flush medications down the
toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is
expired or no longer needed. Consult your pharmacist or local waste disposal company for more
details.

3.PHARMACOKINETICS:
3.1:Absorption

Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in
1 to 2 hours following administration. Plasma levels are proportionate to the dose given; over the dose
range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay
methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours
(range: 6.3–26.9 hours) in healthy adults.

3.2:Distribution

In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the
majority of the binding.

3.3:Metabolism/Elimination

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4

(CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-
hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their
half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-
hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration
were always less than 4%. The reported relative potencies in benzodiazepine receptor binding
experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively,
for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser
potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to
contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is
essentially inactive.

Alprazolam and its metabolites are excreted primarily in the urine.

4.CLINICAL PHARMACOLOGY:
Alprazolam is intermediate acting benzodizepines agent with duration of action 11 to 20 hours.

4.1:MECHANISM OF ACTION:

Alprazolam is classed as a high-potency triazolobenzodiazepine: a benzodiazepine with

a triazole ring attached to its structure. As a benzodiazepine, alprazolam produces a variety of
therapeutic and adverse effects by binding to the GABAA benzodiazepine receptor site and
modulating its function; GABA receptors are the most prolific inhibitory receptor within the
brain. The GABA chemical and receptor system mediates inhibitory or calming effects of
alprazolam on the nervous system. Binding of alprazolam to the GABA A receptor, a chloride ion
channel, enhances the effects of GABA, a neurotransmitter. When GABA binds the
GABAA receptor the channel opens and chloride enters the cell which makes it more resistant to
depolarisation. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce
anxiety.
The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made
up of different combinations of subunits have different properties, different locations within the
brain, and, importantly, different activities with regard to benzodiazepines. Alprazolam and other
triazolobenzodiazepines such as triazolam that have a triazole ring fused to their diazepine ring
appear to have antidepressant properties. This is perhaps due to the similarities shared
with tricyclic antidepressants, as they have two benzene rings fused to a diazepine ring.
Alprazolam causes a marked suppression of the hypothalamic-pituitary-adrenal axis. The
therapeutic properties of alprazolam are similar to other benzodiazepines and
include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic; however, it is used
mainly as an anxiolytic.
Giving alprazolam, as compared to lorazepam, has been demonstrated to elicit a statistically
significant increase in extracellular dopamine D1 and D2 concentrations in the striatum.

4.2:CLINICAL USES:
 Treatment of anxiety, panic attacks, and states of agitation.
 Treatment of neurovegetative symptoms associated with vertigo.
 Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal
 Short-term treatment of insomnia.
 Treatment of muscle spasms.
 Treatment of tetanus, together with other measures of intensive treatment.
 Adjunctive treatment of spastic muscular paresis (paraplegia/tetraplegia) caused by
cerebral or spinal cord conditions such as stroke, multiple sclerosis, or spinal cord injury
(long-term treatment is coupled with other rehabilitative measures)..
  Palliative treatment of stiff person syndrome.
 Pre- or postoperative sedation, anxiolysis or amnesia (e.g., before endoscopic or surgical
procedures).
 Treatment of complications with a hallucinogen crisis and stimulant overdoses and
psychosis.

4.3: INDICATIONS:

Anxiety Disorders

XANAX Tablets (alprazolam) are indicated for the management of anxiety disorder (a condition
corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-IIIR] diagnosis
of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or
tension associated with the stress of everyday life usually does not require treatment with an
anxiolytic.

Anxiety associated with depression is responsive to XANAX.

Panic Disorder

XANAX is also indicated for the treatment of panic disorder, with or without agoraphobia.

Studies supporting this claim were conducted in patients whose diagnoses corresponded closely
to the DSM-III-R/IV criteria for panic disorder .

Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to 4

months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however,
patients with panic disorder have been treated on an open basis for up to 8 months without
apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for
the individual patient.

4.4: CONTRAINDICATIONS:

Use of alprazolam should be avoided, when possible, in individuals with:

 Ataxia
 Severe hypoventilation
 Acute narrow-angle glaucoma
  Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor
of two)
 Severe renal deficiencies (for example, patients on dialysis)
 Liver disorders
 Severe sleep apnea
 Severe depression, particularly when accompanied by suicidal tendencies
 Psychosis
 Pregnancy or breast feeding
 Caution required in elderly or debilitated patients
 Coma or shock
 Abrupt discontinuation of therapy
 Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the
exception of some hallucinogens or stimulants, where it is occasionally used as a
treatment for overdose)
 History of alcohol or drug dependence
 Myasthenia gravis, an autoimmune disorder causing marked fatiguability
 Hypersensitivity or allergy to any drug in the benzodiazepine class

4.5: FDA PREGNANCY CATEGORY:

Alprazolam falls into category D. Alprazolam passes to the baby and may cause harm to
the unborn baby. In addition, the baby may be born with respiratory and other problems if
the mother uses alprazolam while pregnant. However, this medication may sometimes still
help human mothers and their babies more than it might cause harm.

5. DOSAGE SCHEDULE:

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages
given below will meet the needs of most patients, there will be some who require doses greater
than 4 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.

5.1:Anxiety Disorders and Transient Symptoms of Anxiety

Treatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given three
times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of
3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible
effective dose should be employed and the need for continued treatment reassessed frequently.
The risk of dependence may increase with dose and duration of treatment.

5.2:Panic Disorder
The successful treatment of many panic disorder patients has required the use of XANAX at
doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of XANAX
in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed
was approximately 5 to 6 mg daily. Among the approximately 1700 patients participating in the
panic disorder development program, about 300 received XANAX in dosages of greater than 7
mg/day, including approximately 100 patients who received maximum dosages of greater than 9
mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.

5.3:Dose Titration

Treatment may be initiated with a dose of 0.5 mg three times daily. Depending on the response,
the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day.
Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full
expression of the pharmacodynamic effect of XANAX. To lessen the possibility of interdose
symptoms, the times of administration should be distributed as evenly as possible throughout the
waking hours, that is, on a three or four times per day schedule.

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in
patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic
response (ie, a substantial reduction in or total elimination of panic attacks) is achieved,
intolerance occurs, or the maximum recommended dose is attained.

5.4:Dose Maintenance

For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of
dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated
with doses of XANAX greater than 4 mg/day for 3 months were able to taper to 50% of their
total maintenance dose without apparent loss of clinical benefit. Because of the danger of
withdrawal, abrupt discontinuation of treatment should be avoided..

5.6:Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided

In all patients, dosage should be reduced gradually when discontinuing therapy or when
decreasing the daily dosage. Although there are no systematically collected data to support a
specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more
than 0.5 mg every three days. Some patients may require an even slower dosage reduction.
5.7:Dosing in Special Populations

In elderly patients, in patients with advanced liver disease or in patients with debilitating disease,
the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually
increased if needed and tolerated. The elderly may be especially sensitive to the effects of
benzodiazepines. If side effects occur at the recommended starting dose, the dose may be
lowered.

6. DOSE ADJUSTMENT:
Patients with debilitating disease (e.g., severe pulmonary disease):
Immediate-release tablets/ODTs:
Initial dose: 0.25 mg orally 2 or 3 times a day

Extended-release tablets:
Initial dose: 0.5 mg orally once a day

Switching Between Immediate and Extended-release Formulations:

Patients who are currently being treated with divided doses of immediate-release tablets, for
example 3 to 4 times a day, may be switched to extended-release tablets at the same total daily
dose taken once a day.
Dose Reduction:
Immediate-release tablets/ODTs:
Extended-release tablets: Doses should be decreased gradually, with dose decreases of no more
than 0.5 mg every 3 days.

7. ADMINISTRATION GUIDELINES:

7.1:For All Users Of XANAX

To assure safe and effective use of benzodiazepines, all patients prescribed XANAX should be

provided with the following guidance.

1. Inform your physician about any alcohol consumption and medicine you are taking now,
including medication you may buy without a prescription. Alcohol should generally not
be used during treatment with benzodiazepines.
2. Not recommended for use in pregnancy. Therefore, inform your physician if you are
pregnant, if you are planning to have a child, or if you become pregnant while you are
taking this medication.
3. Inform your physician if you are nursing.
4. Until you experience how this medication affects you, do not drive a car or operate
potentially dangerous machinery, etc.
 5. Do not increase the dose even if you think the medication "does not work anymore"
without consulting your physician. Benzodiazepines, even when used as recommended,
may produce emotional and/or physical dependence.
6. Do not stop taking this medication abruptly or decrease the dose without consulting your
physician, since withdrawal symptoms can occur.

7.2:Additional Advice For Panic Disorder Patients

The use of XANAX at doses greater than 4 mg/day, often necessary to treat panic disorder, is
accompanied by risks that you need to carefully consider. When used at doses greater than 4
mg/day, which may or may not be required for your treatment, XANAX has the potential to
cause severe emotional and physical dependence in some patients and these patients may find it
exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration
where the ability of patients to discontinue medication was measured, 7 to 29% of patients
treated with XANAX did not completely taper off therapy. In a controlled postmarketing
discontinuation study of panic disorder patients, the patients treated with doses of XANAX
greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less
than 4 mg/day. In all cases, it is important that your physician help you discontinue this
medication in a careful and safe manner to avoid overly extended use of XANAX.

In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence
and severity of withdrawal reactions when XANAX is discontinued. These are generally minor
but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication
abruptly. Seizure can be life-threatening.

8. ADVERSE DRUG REACTION (ADR):

8.1: Side Effects:

Common alprazolam side effects may include:

 Drowsiness;
 Tired feeling;
 Muscle weakness; or
 Loss of coordination.
 Suppression of REM sleep and Slow wave sleep
 Weak or shallow breathing;
 Severe drowsiness or feeling like you might pass out;
 Depressed mood, thoughts of suicide or hurting yourself;
 Confusion, hallucinations;
 Anxiety, panic attacks, trouble sleeping;
  Hyperactivity aggitation, aggression, hostility;
 Unusual risk-taking behavior; or
 New or worsening seizures.

The sedative effects of alprazolam may last longer in older adults. Accidental falls are common
in elderly patients who take diazepam,. Use caution to avoid falling or accidental injury while
you are taking this medicine. Emergency medical help if you have signs of an allergic reaction to
alprazolam,: difficult breathing; swelling of your face, lips, tongue, or throat

8.2:Adverse Effects:

Alprazolam and other benzodiazepine can cause tolerance, physical dependence, substance use
disorder and benzodiazepine withdrawal syndrome

Tolerance: Benzodiazepine treatment should be discontinued as soon as possible by a slow and

gradual dose reduction regimen.Tolerance develops to the therapeutic effects of
benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result
benzodiazepines are not generally recommended for the long-term management of epilepsy.
Dose increases may overcome the effects of tolerance, but tolerance may then develop to the
higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines
includes uncoupling of receptor sites, alterations in gene expression down-regulation of receptor
sites, and desensitisation of receptor sites to the effect of GABA.

Dependence: Improper or excessive use of alprazolam can lead to dependence. At a particularly

high risk for alprazolam misuse, abuse or dependence are:

People with a history of alcohol or drug abuse or dependence.Alprazolam increases craving for
alcohol in problem alcohol consumers. Alprazolam also increases the volume of alcohol
consumed by problem drinkers.

People with severe personality disorders.

Withdrawal Syndrom: Withdrawal symptoms can occur from standard dosages and also after
short-term use, and can range from insomnia and anxiety to more serious symptoms, including
seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions
and be misdiagnosed. Alprazolam may produce less intense withdrawal symptoms due to its long
elimination half life.

9.DRUG INTERACTION:

9.1:Use With Other CNS Depressants

If XANAX Tablets are to be combined with other psychotropic agents or anticonvulsant drugs,

careful consideration should be given to the pharmacology of the agents to be employed,
particularly with compounds which might potentiate the action of benzodiazepines. The
benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-
administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and
other drugs which themselves produce CNS depression.

9.2:Use With Digoxin

Increased digoxin concentrations have been reported when alprazolam was given, especially in

elderly (>65 years of age). Patients who receive alprazolam and digoxin should therefore be
monitored for signs and symptoms related to digoxin toxicity.

9.3:Use With Imipramine And Desipramine

The steady state plasma concentrations of imipramine and desipramine have been reported to be

increased an average of 31% and 20%, respectively, by the concomitant administration of
XANAX Tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.

Drugs That Inhibit Alprazolam Metabolism Via Cytochrome P450 3A

The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A

(CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the
clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of
this type).

Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of

clinical studies involving alprazolam (caution is recommended during coadministration with
alprazolam)

Fluoxetine

Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of

alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased
measured psychomotor performance.

Propoxyphene

Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%,

decreased clearance by 38%, and increased half-life by 58%.

Oral Contraceptives

Coadministration of oral contraceptives increased the maximum plasma concentration of

alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.
Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies
involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies
with alprazolam or other benzodiazepines (caution is recommended during coadministration with
alprazolam)

Drugs Demonstrated To Be Inducers Of CYP3A

Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of
alprazolam.

10. TOXICOLOGY:
Although not usually fatal when taken alone, a alprazolam overdose is considered a medical
emergency and generally requires the immediate attention of medical personnel.

Overdose of alprazolam is usually manifested by central nervous system depression ranging from

drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy. In
more serious cases, symptoms may include ataxia, diminished reflexes, hypotonia, hypotension,
respiratory depression, coma (rarely), and death (very rarely). Overdose of benzodiazepines in
combination with other CNS depressants (including alcohol) may be fatal and should be closely
monitored.

Management: Following overdose with alprazolam general supportive measures should be

employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be
induced (within one hour) if the patient is conscious. Gastric lavage should be undertaken with
the airway protected if the patient is unconscious. Intravenous fluids should be administered. If
there is no advantage in emptying the stomach, activated charcoal should be given to reduce
absorption. Special attention should be paid to respiratory and cardiac function in intensive care.
General supportive measures should be employed, along with intravenous fluids, and an
adequate airway maintained. Should hypotension develop, treatment may include intravenous
fluid therapy.

Antidote: Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the

complete or partial reversal of the sedative effects of benzodiazepines and may be used in
situations when an overdose with a benzodiazepine is known or suspected. Prior to the
administration of flumazenil, necessary measures should be instituted to secure
airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a
substitute for, proper management of benzodiazepine overdose. The prescribers should be aware
of a risk of seizure in association with flumazenil treatment, particularly in long-term
benzodiazepine users and in cyclic antidepressant overdose. Caution should be observed in the
use of flumazenil in epileptic patients treated with benzodiazepines.
11. PATIENT CARE CONSIDRATION:
Follow all directions on your prescription label. Your doctor may occasionally change your dose.
Do not take this medicine in larger or smaller amounts or for longer than
recommended.Alprazolam may be habit-forming. Misuse of habit-forming medicine can cause
addiction, overdose, or death.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring
spoon or medicine cup. Do not use not a kitchen spoon. If you do not have a dose-measuring
device, ask your pharmacist for one.Alprazolam should be used for only a short time. Do not
take this medicine for longer than 4 months without your doctor's advice.Do not stop using this
medicine suddenly, or you could have increased seizures or unpleasant withdrawal symptoms.
Ask your doctor how to safely stop using this medicine.Call your doctor at once if you feel that
this medicine is not working as well as usual, or if you think you need to use more than usual.

Store at room temperature away from moisture, heat, and light. Keep track of your medicine.
Alprazolam is a drug of abuse and you should be aware if anyone is using your medicine
improperly or without a prescription.

12. PATIENT & FAMILY EDUCATION:

To assure the safe and effective use of Benzodiazepine patients should be informed that, since
benzodiazepines may produce psychological and physical dependence, it is advisable that they
consult with their physician before either increasing the dose or abruptly discontinuing this drug.
The risk of dependence increases with duration of treatment; it is also greater in patients with a
history of alcohol or drug abuse.

Patients should be advised against the simultaneous ingestion of alcohol and other CNS-
depressant drugs during alprazolam therapy. As is true of most CNS-acting drugs, patients
receiving diazepam should be cautioned against engaging in hazardous occupations requiring
complete mental alertness, such as operating machinery or driving a motor vehicle.

13. REFERENCES:
1. Basic & Clinical Pharmacology written by G.Katzung and J.Trevor 12th edition page 389-400

2. British Pharmacopoeia.

3. United State Pharmacopoeia.

4. https://en.wikipedia.org/wiki/Alprazolam#Chemistry