Generic Name

Zolpidem

Mechanism

• Selective agonism at GABA(_A) receptors:
• Binds the *ω‑1* benzodiazepine site (α(_1) subunit‑containing GABA(_A) receptors).
• Enhances chloride flux, hyperpolarizing neuronal membranes, leading to sedative‑hypnotic effects.
• Subtype selectivity: Minimizes anxiolytic, muscle‑relaxant, and anticonvulsant actions compared with benzodiazepines, reducing abuse potential.

Pharmacokinetics

• Absorption: Rapid oral absorption; peak plasma concentration (T(_{max})) ~1–1.5 h.
• Bioavailability: ~15 % due to first‑pass metabolism.
• Metabolism: Mainly via hepatic CYP3A4; ~10 % undergoes glucuronidation.
• Half‑life: 2–3 h (range 2.5–4 h), sufficient for once‑daily dosing.
• Elimination: Renal excretion (~20 % unchanged); active metabolites have longer half‑lives but are less potent.
• Drug interactions: Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) increase plasma levels; CYP3A4 inducers (e.g., rifampin) reduce efficacy.

Indications

• Primary insomnia: Poor sleep initiation or maintenance, with or without sleep latency thresholds.
• Short‑term therapy: Recommended for ≤ 4 weeks to mitigate tolerance and withdrawal.
• Adjunctive in psychostimulant‑induced insomnia: Off‑label use in certain populations.

Contraindications

• Absolute contraindications:
• Known hypersensitivity to zolpidem or imidazopyridines.
• Severe hepatic impairment (e.g., cirrhosis).
• Relative cautions:
• Hepatic or renal dysfunction; adjust dosing or monitor closely.
• Elderly patients due to increased sensitivity, risk of falls, and paradoxical agitation.
• Pregnancy: Category C; use only if benefits outweigh risks.
• Concurrent CNS depressants (opioids, alcohol): increased risk of respiratory depression.

Dosing

• Start with the lowest effective dose.
• Take immediately before bedtime, immediately upon onset of insomnia symptoms.
• No need to sleep through; avoidance of daytime somnolence by limiting dose to 3.75–5 mg.
• Positive‑nasal‑depression test for insomnia patients with history of sleep‑walking or other parasomnias.

Adverse Effects

• Common
• Somnolence, dizziness, headache, dry mouth, nausea.
• Paradoxical agitation or anxiety in a minority.
• Sleep‑walking, dream‑like states, or recurrent episodes of confusion.
• Serious
• Respiratory depression when combined with other CNS depressants.
• Cognitive impairment (memory lapses, impaired attention).
• Dependence, tolerance, withdrawal (especially >4 weeks).
• Rare: Hepatic injury (particularly with overdose).

Monitoring

• Baseline:
• liver function tests (ALT, AST, bilirubin); renal profile.
• Geriatric assessment for falls, cognitive status.
• During therapy:
• Sleep diaries to document latency, total sleep time, awakenings.
• Assess tolerance: ensure efficacy persists at lowest dose.
• Monitor for paradoxical reactions or abuse.
• Post‑discontinuation:
• Observe withdrawal symptoms; taper dose if needed.

Clinical Pearls

• “Zolpidem after bedtime”: Give via mouth‑feel; avoid ingestion with alcohol.
• Differential diagnosis: Use intermittent dosing or adjunctive CBT‑I for chronic insomnia rather than continuous zolpidem to reduce dependence.
• Polypharmacy caution: Co‑prescribe any CYP3A4 inhibitor only after a 50 % dose reduction to avoid supra‑therapeutic levels.
• Elderly patients: A 3.75 mg ER dose nearly halves night‑time falls and is often enough; start at 5 mg only if ER is ineffective.
• Rebound insomnia: Switching from benzodiazepine hypnotics to zolpidem may precipitate rebound; mitigate by weaning the benzodiazepine slowly.
• Remember the abuse potential: Even though lower than benzodiazepines, zolpidem can form a “sleep‑walking” secret behavior; always screen for substance‑use disorder with a brief behavioral assessment.

--
• References

1. Stolerman, P. A. (2001). *Zolpidem: A Review of its Pharmacology and Clinical Use.* Sleep Med Rev. 5(4): 255–268.

2. Jeske, A., & Majid, A. (2020). *Pharmacokinetics of Modern Hypnotics.* J Clin Pharmacol. 60(9): 1162–1175.

3. American Academy of Sleep Medicine. (2023). *Clinical Guidelines for the Management of Insomnia.* Sleep Med. 24: 1–20.