Xanax - Drug Monograph

Introduction

Xanax (alprazolam) is a benzodiazepine medication primarily indicated for the management of anxiety disorders and panic disorder. As a Schedule IV controlled substance, it possesses significant abuse potential and requires careful clinical oversight. First approved by the FDA in 1981, Xanax remains one of the most commonly prescribed psychotropic medications in the United States despite growing concerns about dependence and misuse.

Mechanism of Action

Xanax exerts its therapeutic effects through potentiation of gamma-aminobutyric acid (GABA) neurotransmission. It binds to specific sites on the GABA-A receptor complex, enhancing GABA's inhibitory effects by increasing chloride ion channel opening frequency. This hyperpolarizes neuronal membranes, reducing neuronal excitability throughout the central nervous system. The drug demonstrates particular affinity for alpha-1 and alpha-2 subunit-containing GABA-A receptors, contributing to both its anxiolytic and sedative properties.

Indications

FDA-approved indications:

• Management of anxiety disorders (generalized anxiety disorder)
• Treatment of panic disorder, with or without agoraphobia
• Short-term relief of anxiety symptoms

Off-label uses (require careful risk-benefit assessment):

• Adjuvant treatment for depression with anxiety features
• Chemotherapy-induced nausea and vomiting
• Preoperative anxiety

Dosage and Administration

• Geriatric patients: Initial dose 0.25 mg BID-TID
• Hepatic impairment: Reduce dose by 50% or avoid use
• Renal impairment: Caution advised; consider reduced dosing
• CYP3A4 poor metabolizers: Reduce initial dose by 50%

Pharmacokinetics

• Absorption: Rapid and complete (90% bioavailability); Tmax 1-2 hours
• Distribution: Vd 0.8-1.3 L/kg; 80% protein binding
• Metabolism: Extensive hepatic metabolism via CYP3A4 to active metabolites (α-hydroxyalprazolam) and inactive metabolites
• Elimination: Half-life 11-16 hours; primarily renal excretion (80% as metabolites)
• Steady-state: Achieved within 5-7 days with multiple dosing

Contraindications

• Hypersensitivity to alprazolam or other benzodiazepines
• Acute narrow-angle glaucoma
• Concurrent use with strong CYP3A4 inhibitors (ketoconazole, itraconazole)
• Significant respiratory depression
• Myasthenia gravis
• Severe hepatic impairment
• Pregnancy (except in rare circumstances)

Warnings and Precautions

Additional warnings:

• Risk of dependence and withdrawal: Avoid abrupt discontinuation
• Sedation and impaired coordination: Caution with driving or operating machinery
• Paradoxical reactions: May include excitement, stimulation, or rage
• Depression and suicidal ideation: Monitor high-risk patients
• Elderly patients: Increased risk of falls and cognitive impairment
• Pregnancy: Potential neonatal withdrawal syndrome and floppy infant syndrome

Drug Interactions

• CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): ↑ alprazolam levels
• Opioids: ↑ CNS depression risk
• Alcohol: Additive CNS depression
• Oral contraceptives: May ↓ alprazolam clearance

• Other CNS depressants (antipsychotics, antidepressants, anticonvulsants)
• Digoxin: Possible ↑ digoxin levels
• CYP3A4 inducers (carbamazepine, phenytoin, rifampin): ↓ alprazolam levels

Adverse Effects

• Sedation (41%)
• Fatigue (15%)
• Impaired coordination (12%)
• Memory impairment (10%)

• Dizziness, speech difficulties, depression
• Constipation, changes in appetite
• Hypotension, blurred vision

• Respiratory depression
• Dependence and withdrawal syndrome
• Paradoxical reactions
• Hepatic enzyme elevations
• Blood dyscrasias (rare)

Monitoring Parameters

• Efficacy: Anxiety scales (HAM-A), panic attack frequency
• Safety: Respiratory rate, sedation level, coordination
• Mental status: Mood changes, depression, suicidal ideation
• Signs of misuse or diversion
• Withdrawal symptoms during taper
• Renal and hepatic function (periodically)
• Fall risk assessment in elderly patients

Patient Education

• Take exactly as prescribed; do not increase dose without consultation
• Avoid alcohol and other CNS depressants
• Do not abruptly stop medication due to withdrawal risk
• Report signs of depression or suicidal thoughts immediately
• Use caution when driving or operating machinery
• Inform all healthcare providers of Xanax use
• Store securely to prevent misuse by others
• Use reliable contraception during treatment
• Understand potential for dependence with long-term use

References

1. FDA prescribing information: Xanax (alprazolam) tablets. Revised 2021. 2. Ashton CH. Benzodiazepines: how they work and how to withdraw. 2002. 3. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Panic Disorder. 2009. 4. Griffiths RR, et al. Principles of Drug Addiction Treatment. NIDA. 2018. 5. Lader M. Benzodiazepines revisited—will we ever learn? Addiction. 2011;106(12):2086-2109. 6. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th Edition. 7. Lexicomp Online, Alprazolam Monograph. Accessed 2023.