Alprazolam Drug Profile mechanism of action

Alparazolam drug ADR Therapeutic uses

1. Alprazolam Drug Profile
Drug Class: Benzodiazepine, short-acting anxiolytic and sedative-hypnotic.
Mechanism of Action: Alprazolam, like other benzodiazepines, exerts its effects primarily by
enhancing the activity of gamma-aminobutyric acid (GABA), the major inhibitory
neurotransmitter in the central nervous system (CNS). It binds to specific benzodiazepine
receptors on the GABA-A receptor complex, increasing the frequency of chloride channel
opening. This leads to an influx of chloride ions, hyperpolarizing the neuron and making it less
excitable, thereby producing anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant
effects.
Boxed Warnings (FDA Black Box Warnings)
The FDA has issued boxed warnings for alprazolam due to significant risks:
Risks from Concomitant Use with Opioids: Concomitant use of benzodiazepines,
including alprazolam, and opioids may result in profound sedation, respiratory
depression, coma, and death. Reserve concomitant prescribing for use in patients for
whom alternative treatment options are inadequate. Limit dosages and durations to the
minimum required. Follow patients for signs and symptoms of respiratory depression
and sedation.
Abuse, Misuse, and Addiction: The use of benzodiazepines, including alprazolam,
exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or
death. Before prescribing alprazolam and throughout treatment, assess each patient's
risk for abuse, misuse, and addiction.
Dependence and Withdrawal Reactions: The continued use of alprazolam may lead to
clinically significant physical dependence. The risks of dependence and withdrawal
increase with longer treatment duration and higher daily dose. Abrupt discontinuation
or rapid dosage reduction of alprazolam after continued use may precipitate acute
withdrawal reactions, which can be life-threatening (e.g., seizures, delirium). To reduce
the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or
reduce the dosage.
Therapeutic Indications
Alprazolam is FDA-approved for the following conditions:
Generalized Anxiety Disorder (GAD): For the acute treatment of generalized anxiety
disorder in adults.

2. Panic Disorder: For the treatment of panic disorder, with or without agoraphobia, in
adults.
Note: Alprazolam is intended for short-term use due to the risks of dependence and
withdrawal.
Dosage Forms Available
Alprazolam is available in various oral formulations:
Immediate-Release (IR) Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg. (Brand name example:
Xanax)
Extended-Release (XR) Tablets: 0.5 mg, 1 mg, 2 mg, 3 mg. (Brand name example: Xanax
XR)
Orally Disintegrating Tablets (ODT): 0.25 mg, 0.5 mg, 1 mg, 2 mg. (Brand name
example: Niravam)
Oral Solution/Concentrate: 1 mg/mL.
Dosage and Administration
Dosage must be individualized and adjusted based on patient response and tolerance. The
lowest effective dose should be used for the shortest duration possible.
Adults:
Generalized Anxiety Disorder (IR Tablets/ODT):
oInitial Dose: 0.25 mg to 0.5 mg orally, three times daily.
oTitration: Dosage may be increased every 3 to 4 days, by no more than 1
mg/day.
oMaximum Recommended Daily Dose: 4 mg per day, given in divided doses.
Panic Disorder (IR Tablets/ODT):
oInitial Dose: 0.5 mg orally, three times daily.
oTitration: Dosage may be increased every 3 to 4 days in increments of no more
than 1 mg per day, until a satisfactory therapeutic response is achieved or until
side effects preclude further increases.
oAverage Daily Dose: 5 mg to 6 mg per day.
oMaximum Daily Dose: 10 mg per day.

3. Panic Disorder (XR Tablets):
oInitial Dose: 0.5 mg to 1 mg orally once daily, preferably in the morning.
oTitration: The daily dose may be increased at intervals of 3 to 4 days in
increments of no more than 1 mg per day.
oMaintenance Dose: 3 mg to 6 mg orally once daily.
oMaximum Daily Dose: 10 mg per day.
Geriatric Patients or Debilitated Patients:
Initial Dose: Lower doses are recommended due to increased sensitivity to
benzodiazepines.
oIR Tablets/ODT: 0.25 mg orally, two or three times daily.
oXR Tablets: 0.5 mg orally once daily.
Dosage may be increased gradually if needed and tolerated.
Patients with Hepatic Impairment:
Severe Hepatic Dysfunction: Use with caution.
oIR Tablets/ODT: Initial dose 0.25 mg orally two or three times daily.
oXR Tablets: Initial dose 0.5 mg orally once daily.
Discontinuation or Dosage Reduction:
To minimize withdrawal symptoms, alprazolam should be tapered gradually.
The daily dosage should be decreased by no more than 0.5 mg every three days. Some
patients may require an even slower dosage reduction.
If withdrawal symptoms appear during tapering, the dosage should be reinstituted and
the tapering schedule resumed at a slower rate.
Administration:
IR Tablets: Can be taken with or without food.
XR Tablets: Should be swallowed whole; do not crush, chew, or break.
ODT: Immediately upon opening the blister, with dry hands, remove the tablet and
place it on top of the tongue. It will disintegrate rapidly in saliva and can be swallowed
with or without water.

4. Oral Solution: Measure the dose accurately using the provided calibrated dropper or
measuring device.
Precautions
CNS Depression: Alprazolam causes dose-related CNS depression, ranging from mild
drowsiness to profound sedation, respiratory depression, and coma. Patients should be
cautioned against engaging in hazardous occupations (e.g., driving, operating
machinery) until they know how the drug affects them.
Risk of Abuse, Misuse, and Addiction: Alprazolam is a Schedule IV controlled substance.
Patients should be carefully monitored for signs of abuse or addiction. Prescribe the
lowest effective dose for the shortest duration possible.
Physical Dependence and Withdrawal: Even at recommended doses, physical
dependence can develop. Abrupt discontinuation or rapid tapering can lead to severe
and potentially life-threatening withdrawal symptoms (e.g., seizures, hallucinations,
tremor, severe anxiety, psychosis, suicidal ideation). Taper slowly.
Respiratory Depression: Use with extreme caution in patients with pulmonary disease
(e.g., COPD, sleep apnea) due to the risk of respiratory depression.
Depression and Suicidal Ideation: Benzodiazepines, including alprazolam, may worsen
depression and can potentially increase suicidal thoughts or behaviors in depressed
patients. Use with caution in patients with depression.
Mania/Hypomania: Alprazolam may precipitate hypomania or mania in patients with
latent bipolar disorder.
Hepatic Impairment: Alprazolam is extensively metabolized by the liver (primarily via
CYP3A4). Impaired liver function can significantly reduce clearance, increasing plasma
levels and the risk of adverse effects. Lower doses are recommended in severe hepatic
impairment.
Renal Impairment: Use with caution in patients with impaired renal function.
Elderly and Debilitated Patients: More susceptible to the CNS depressant effects (e.g.,
sedation, ataxia, falls). Lower starting doses are recommended.
Paradoxical Reactions: Rare paradoxical reactions (e.g., aggression, agitation,
hallucinations, rage) have been reported, particularly in children and the elderly.
Glaucoma: Contraindicated in patients with acute narrow-angle glaucoma. May be used
in patients with open-angle glaucoma receiving appropriate therapy.

5. Pregnancy: Benzodiazepines can potentially cause fetal harm when administered to
pregnant women. If used during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to the fetus.
Neonates born to mothers using benzodiazepines late in pregnancy may suffer from
sedation and withdrawal symptoms.
Lactation: Alprazolam is excreted in human milk. Breastfeeding is generally not
recommended during alprazolam therapy due to the potential for sedation and feeding
difficulties in the infant.
Side Effects
The most common side effects are dose-related CNS depression.
Very Common (≥ 10%):
Sedation/Drowsiness
Ataxia (lack of muscle coordination)
Fatigue
Dysarthria (slurred speech)
Memory impairment
Constipation
Common (1-9%):
Dizziness, lightheadedness
Headache
Blurred vision
Insomnia
Nervousness, anxiety
Confusion
Tremor
Changes in appetite/weight (increase or decrease)
Nausea, vomiting
Diarrhea

6. Dry mouth
Nasal congestion
Musculoskeletal weakness
Hypotension (low blood pressure)
Decreased libido
Rash, dermatitis
Less Common / Serious Side Effects (< 1% or Post-marketing reports):
Psychiatric: Paradoxical reactions (e.g., agitation, irritability, aggression, hostility, rage,
hallucinations), depression, suicidal ideation, mania, hypomania, depersonalization.
Neurological: Seizures (especially upon withdrawal), dystonia, abnormal involuntary
movements.
Gastrointestinal: Jaundice, elevated liver enzymes, hepatitis, hepatic failure.
Dermatologic: Stevens-Johnson syndrome, angioedema, photosensitivity reaction.
Endocrine: Hyperprolactinemia, gynecomastia, galactorrhea.
Other: Allergic reactions (rare but serious, including anaphylaxis), urinary retention.
Drug Interactions and Their Management
Alprazolam is primarily metabolized by cytochrome P450 3A4 (CYP3A4). Interactions primarily
involve drugs that inhibit or induce this enzyme, as well as other CNS depressants.
1.Opioids (e.g., oxycodone, hydrocodone, fentanyl):
oInteraction: Concomitant use significantly increases the risk of profound
sedation, respiratory depression, coma, and death. This is a boxed warning.
oManagement: Avoid concomitant use if possible. If unavoidable, prescribe the
lowest effective doses and shortest durations of both drugs. Closely monitor
patients for signs of respiratory depression and sedation. Advise patients and
caregivers on these risks and symptoms. Consider prescribing naloxone for
opioid overdose reversal.
2.Other CNS Depressants (e.g., alcohol, other benzodiazepines, barbiturates,
antidepressants, antipsychotics, sedative antihistamines, muscle relaxants):

7. oInteraction: Additive CNS depressant effects, leading to increased sedation,
dizziness, impaired coordination, and respiratory depression.
oManagement: Avoid concomitant use if possible. If combined, use lower doses
of one or both agents and monitor patients closely for excessive sedation. Advise
patients to avoid alcohol.
3.CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, nefazodone,
ritonavir, atazanavir, grapefruit juice):
oInteraction: These drugs decrease alprazolam metabolism, leading to increased
and prolonged plasma concentrations of alprazolam and an increased risk of
adverse effects (e.g., sedation, respiratory depression).
oManagement:
Potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole):
Concomitant use is contraindicated.
Moderate CYP3A4 inhibitors (e.g., nefazodone, fluoxetine, fluvoxamine,
clarithromycin, erythromycin, diltiazem, verapamil, amiodarone): Use
with caution. Consider a significant reduction in alprazolam dose (e.g.,
50% or more, depending on the inhibitor potency). Monitor closely for
increased alprazolam effects.
Grapefruit Juice: Advise patients to avoid consuming grapefruit or
grapefruit juice, as it can inhibit CYP3A4 and increase alprazolam levels.
4.CYP3A4 Inducers (e.g., carbamazepine, phenytoin, phenobarbital, rifampin, St. John's
Wort):
oInteraction: These drugs increase alprazolam metabolism, leading to decreased
plasma concentrations of alprazolam and potentially reduced therapeutic
efficacy.
oManagement: Monitor for decreased efficacy of alprazolam. An increase in
alprazolam dose may be necessary.
5.Digoxin:
oInteraction: There have been reports of increased digoxin concentrations when
co-administered with alprazolam, although the mechanism is not fully clear.
oManagement: Monitor digoxin levels in patients receiving both medications.
6.Imipramine and Desipramine:

8. oInteraction: Concurrent administration of alprazolam with imipramine or
desipramine has been reported to result in steady-state plasma concentrations
of imipramine and desipramine increasing by 31% and 20% respectively.
oManagement: Monitor for increased effects of these tricyclic antidepressants
and adjust doses if necessary.
7.Cigarette Smoking:
oInteraction: Smoking can induce CYP1A2, which may lead to reduced alprazolam
concentrations, though alprazolam is primarily metabolized by CYP3A4. Some
studies suggest alprazolam clearance may be increased by up to 50% in smokers.
oManagement: Patients who smoke may require higher doses of alprazolam.