Alprazolam - Drug Monograph

Introduction

Alprazolam is a short-acting benzodiazepine derivative primarily used for the management of anxiety disorders and panic disorder. Marketed under the brand name Xanax among others, it is one of the most commonly prescribed psychotropic medications in the United States. As a Schedule IV controlled substance, alprazolam carries significant potential for dependence and abuse, requiring careful clinical consideration.

Mechanism of Action

Alprazolam 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 neurons and reduces neuronal excitability throughout the central nervous system, resulting in anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant properties.

Indications

FDA-approved indications:

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

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

• Adjuvant treatment for depression with anxiety features
• Chemotherapy-induced nausea and vomiting
• Premenstrual dysphoric disorder

Dosage and Administration

• Initial dose: 0.25-0.5 mg three times daily
• Maximum dose: 4 mg/day in divided doses

• Initial dose: 0.5 mg three times daily
• Maintenance dose: 1-10 mg/day in divided doses
• Average effective dose: 5-6 mg/day

• Geriatric patients: Initial dose 0.25 mg two or three times daily
• Hepatic impairment: Reduce dose by 50-60%
• Renal impairment: No specific guidelines; use caution
• Debilitated patients: Initiate with lowest possible dose

• Oral administration with or without food
• Tablets should be swallowed whole
• Avoid grapefruit juice (affects metabolism)

Pharmacokinetics

• Volume of distribution: 0.8-1.3 L/kg
• Protein binding: 80% primarily to albumin
• Crosses blood-brain barrier and placenta; excreted in breast milk

• Half-life: 11-16 hours (shorter than other benzodiazepines)
• Elimination primarily renal (80% as metabolites)
• Clearance: 0.7-1.5 mL/min/kg

Contraindications

• Hypersensitivity to alprazolam or other benzodiazepines
• Acute narrow-angle glaucoma
• Concurrent use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole)
• Significant respiratory depression
• Acute alcohol intoxication
• Myasthenia gravis
• Severe hepatic impairment
• Pregnancy (first trimester)

Warnings and Precautions

• Risk of abuse, misuse, and addiction which can lead to overdose or death
• Risk of dependence with continued use; taper gradually to avoid withdrawal

• Paradoxical reactions including agitation, rage, and insomnia
• Impaired cognitive and motor performance
• Depression and suicidal ideation
• Elderly patients at increased risk of falls and cognitive impairment
• Respiratory depression, especially in patients with pulmonary disease
• Withdrawal seizures with abrupt discontinuation

Drug Interactions

• CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): ↑ alprazolam levels
• CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): ↓ alprazolam levels
• Opioids: ↑ risk of profound sedation, respiratory depression, coma, death
• Alcohol: Additive CNS depression
• Other CNS depressants: Enhanced sedative effects

• Oral contraceptives: May inhibit metabolism
• Fluoxetine, nefazodone: May increase alprazolam concentrations
• Digoxin: Possible increased digoxin levels
• Theophylline: May reduce alprazolam efficacy

Adverse Effects

• Drowsiness/sedation (41%)
• Lightheadedness (21%)
• Depression (14%)
• Headache (13%)
• Constipation (11%)
• Dry mouth (11%)

• Confusion
• Memory impairment
• Ataxia
• Slurred speech
• Fatigue
• nausea

• Respiratory depression
• Dependence and withdrawal syndrome
• Suicidal ideation
• Jaundice
• Severe dermatological reactions
• Blood dyscrasias

Monitoring Parameters

• Comprehensive medical and psychiatric history
• Substance use history
• Liver function tests
• Renal function
• Assessment of fall risk in elderly

• Therapeutic efficacy (anxiety/panic symptoms)
• Signs of sedation and cognitive impairment
• Development of dependence behaviors
• Withdrawal symptoms during taper
• Respiratory function in susceptible patients
• Mood changes including depression
• Periodic assessment of continued need

• Evaluation of misuse, abuse, and addiction
• Assessment of functional status

Patient Education

• Take exactly as prescribed; do not increase dose without consultation
• Avoid alcohol and other CNS depressants
• Do not operate heavy machinery until effects are known
• Potential for dependence with long-term use
• Never share medication with others
• Store securely to prevent misuse by others

• Do not stop abruptly; taper under medical supervision
• Recognize withdrawal symptoms: anxiety, insomnia, tremors, seizures
• Seek immediate medical attention for severe symptoms

• Pregnancy: Discuss risks and need for contraception
• Breastfeeding: Not recommended
• Elderly: Increased risk of falls; rise slowly from sitting position

• Take as soon as remembered unless close to next dose
• Do not double doses

References

1. FDA prescribing information: Xanax (alprazolam) tablets 2. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.) 3. Ashton CH. Benzodiazepines: how they work & how to withdraw. 2002 4. Greenblatt DJ, et al. Clinical pharmacokinetics of alprazolam. Clin Pharmacokinet. 1993;24(6):453-471 5. Baldwin DS, et al. Benzodiazepines: risks and benefits. Adv Psych Treat. 2013;19:237-243 6. Lader M. Benzodiazepines revisited—will we ever learn? Addiction. 2011;106(12):2086-2109 7. National Institute on Drug Abuse. Benzodiazepines and Opioids. 2021 8. UpToDate. Alprazolam: Drug information. 2023 9. Micromedex Solutions. Alprazolam monograph. 2023 10. Clinical Pharmacology [database online]. Alprazolam. 2023