Alprazolam
Alprazolam
Generic Name
Alprazolam
Mechanism
Alprazolam is a benzodiazepine that potentiates inhibitory neurotransmission.
• Enhances the activity of the γ‑aminobutyric acid (GABA)‑A receptor complex.
• Increases chloride ion influx, hyperpolarizing neuronal membranes.
• Produces anxiolytic, sedative‑hypnotic, anticonvulsant, and muscle‑relaxant effects.
Pharmacokinetics
- Absorption – Rapid, peak plasma levels within 1–2 h; bioavailability ≈ 96 %.
- Distribution – Highly protein‑bound (~ 94 %); crosses blood–brain barrier and placenta.
- Metabolism – Primarily CYP3A4‑mediated hydroxylation → inactive 3‑hydroxy derivatives.
- Excretion – Renal (≈ 20 %) and biliary routes; half‑life 11–16 h (range 6–27 h).
- Drug interactions – CYP3A4 inhibitors ↑ levels; CYP3A4 inducers ↓ levels; potentiate CNS depressants.
Indications
- Generalized anxiety disorder (short‑term or as-needed).
- Panic disorder (maintenance and acute relief).
- Anxiogenic states precipitated by antidepressants or heavy alcohol withdrawal.
- Adjunct to tertiary pain management in certain postoperative cases (off‑label).
Contraindications
- Absolute contraindications: Acute narrow‑angle glaucoma, severe hepatic impairment, Concomitant use of mono‑amine oxidase inhibitors (within 14 days).
- Warnings:
- Risk of dependence, tolerance, and withdrawal.
- Cognitive/psychomotor impairment—avoid driving, operating machinery.
- Pregnancy (Category D) – potential fetal harm; use only if benefits outweigh risks.
- Lactation – minimal evidence; avoid with nursing infants.
Dosing
| Condition | Initial dose | Titration | Max dose | Form | Special Populations |
| GAD / Panic | 0.25 mg PO BID | ↑0.25 mg every 48 h as needed | 4 mg/day | Immediate‑release tablets (0.25/0.5 mg) | Elderly: start 0.25 mg BID; consider slower titration |
| Acute panic | 0.5–1 mg PO | repeat as needed | 2 mg PO TID | XR‑tablet 1.5‑2 mg | Children < 12 y: not approved |
| Off‑label • pain | 0.5–1 mg PO as needed | — | 4 mg/day | -- | Renal impairment: monitor; Hepatic impairment: ↓ dose |
*Take with food to reduce GI upset.*
Adverse Effects
- Common: Drowsiness, dizziness, fatigue, impaired cognition, dry mouth, blurred vision.
- Less common: Paradoxical agitation, irritability, ataxia.
- Serious: Respiratory depression (especially in overdose or with opioids), withdrawal seizures, severe depression, suicidal ideation, hepatotoxicity (rare).
Monitoring
- Clinical: Anxiety score (HAM-A, GAD‑7), sedation level, functional capacity.
- Laboratory: Liver function tests (baseline, every 4–6 wk if chronic use).
- Safety: Watch for withdrawal symptoms upon abrupt cessation; taper 2–4 weeks.
- Therapeutic drug monitoring: Not routine but advisable in cases of suspected overdose or drug interactions.
Clinical Pearls
1. Taper first, don't stop abruptly – a 2–4 wk taper reduces withdrawal risk; consider 0.5 mg per week decrement.
2. Avoid combining with opioids or alcohol – synergistic CNS depression can precipitate fatal hypoventilation.
3. Use lowest effective dose for shortest duration – guidelines recommend ≤2 weeks for acute panic; extended use warrants psychotherapy integration.
4. Consider pharmacogenomics – CYP3A4 polymorphisms can dramatically alter clearance; dose adjustments may be needed in poor metabolizers.
5. In pregnancy, use instead of tricyclics – limited data suggests benzodiazepines are preferable if treatment is unavoidable, but still carry risks.
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