Alprazolam (Xanax®, Niravam®) – GABAA Receptor Positive Allosteric Modulator

Overview

Alprazolam is a short-acting benzodiazepine medication used in the treatment of anxiety disorders.  It acts as a positive allosteric modulator of synaptic GABAA receptors, increasing neuronal hyperpolarization and CNS depressant effects.  Alprazolam is the only benzodiazepine with significant antidepressant efficacy.

Alprazolam

Alprazolam Visual Summary

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Indications and Dosing

Anxiety Disorders

  • General Anxiety Disorder: 0.25 – 1.3 mg PO TID; start low, titrate up, taper D/C
  • Short-Term Anxiety Symptom Relief:  0.25 – 1.3 mg PO TID; start low, titrate up, taper D/C
  • Anxiety w/ Depression:  0.25 – 1.3 mg PO TID; start low, titrate up, taper D/C
  • Panic Disorder: 0.5 – 3 mg PO TID (IR), or 3-6 mg PO QD (ER); start low, titrate up, taper D/C; divide dose more frequently if needed

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Pharmacology

Physiology: Alprazolam, like other benzodiazepines, functions through allosteric potentiation of synaptic GABAA receptors.  These ligand-gated ion channels mediate inhibitory neurotransmission at GABAergic synapses, conducting chloride into the post-synaptic neuron and hyperpolarizing the surrounding membrane.  By increasing the frequency of channel opening, benzodiazepines facilitate the hyperpolarization of neuronal membranes and contribute to decreased cortical excitability.

alprazolam_mech

Mechanism of Alprazolam

Targets: GABAA receptor (chloride channels), between α, γ subunits

Half-life: 11h (IR), 13.5 h (ER)

Excretion: Renal

Metabolism: Hepatic metabolism; CYP3A4 Substrate, CYP3A4 weak inhibitor

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Safety

Serious Adverse Events

  • Respiratory Depression (boxed warning regarding risk w/ concomitant opioid use)
  • Dependency/Abuse (label warning)
  • Seizure (label warning regarding D/C)
  • Mania/Hypomania (rare, post-market surveillance)
  • SJS/Angioedema (rare, post-market surveillance)
  • Hypotension/Tachycardia (>5% in clinical trials)
  • Hepatotoxicity (rare, post-market surveillance)
  • Psychomotor Impairment (>5% in clinical trials)
  • Drowsiness & Sedation (>5% in clinical trials)

Contraindications

  • Alprazolam Hypersensitivity
  • Concurrent Opioid Use (when possible)
  • Acute Narrow-Angle Glaucoma
  • Concurrent CYP3A4 Inhibitors
  • Avoid Abrupt D/C

Pregnancy

  • FDA Pregnancy Category D (positive evidence of fetal toxicity risk in humans)

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Evidence-Based Medicine

Foundational Studies

  • 1973-1977: early open-label pilot studies of alprazolam (U-31,889) in inpatient and outpatient patients with anxiety, depressed patients, and alcoholic anxious patients
  • 1979-1983: double-blind/placebo-controlled trials for anxiety (Aden &Thein, Chouinard, Cohn, Davison, Griess & Fogari, Maletzky, Rickels)
  • 1982: study showed efficacy in depression
  • 1981: Xanax FDA Approval
  • 1982: studies (Chouinard, Sheehan) demonstrated efficacy in panic & phobic disorders
  • Review: 1983 survey of early clinical trials

Cutting-Edge Alprazolam Research

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Drug Cost

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Citations

  1. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037
  2. Epocrates Rx Online [Internet database]. San Mateo (CA): Epocrates, Inc. 2003. Retrieved at mobile.epocrates.com. Web-based; continuous content updates. Accessed 2018 May 21.
  3. “Prescription Prices, Coupons & Pharmacy Information – GoodRx.” Prescription Prices, Coupons & Pharmacy Information – GoodRxhttp://www.goodrx.com
  4. “DailyMed.” U.S. National Library of Medicine, National Institutes of Health, dailymed.nlm.nih.gov/dailymed/.
  5. F. Petty, M.H. Trivedi, M. Fulton, A.J. Rush. Benzodiazepines as antidepressants: Does GABA play a role in depression? Biol Psychiatry, 38 (1995), pp. 578-591
  6. Lexi-Comp OnlineTM , AlprazolamTM , Hudson, Ohio: Lexi-Comp, Inc.; June 13th, 2018
  7. Straw RN. Brief review of published alprazolam clinical studies. British Journal of Clinical Pharmacology. 1985;19(Suppl 1):57S-59S.
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