Zopiclone
Zopiclone
Generic Name
Zopiclone
Mechanism
- Benzodiazepine‑receptor agonist that binds to the γ‑aminobutyric acid A (GABAA) receptor complex.
- Acts as a positive allosteric modulator:
- Enhances chloride influx, hyperpolarizing neuronal membranes.
- Increases the frequency of channel opening when GABA is present.
- Lacks significant affinity for benzodiazepine‑related receptors (e.g., 5‑HT2, α2 adrenergic), giving it a distinct profile of minimal anxiolytic/euphoric effects but potent hypnotic action.
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Pharmacokinetics
| Parameter | Details |
| Absorption | Rapid, peak plasma concentration at ~1–2 h post‑dose. Oral bioavailability: ~80 %. |
| Distribution | Volume of distribution: 1.6 L·kg⁻¹; highly protein‑bound (~95 %). |
| Metabolism | Hepatic via CYP3A4 → primarily 16‑hydroxy metabolite (inactive). Minor CYP2E1, CYP2C9 involvement. |
| Half‑life | Elimination half‑life: 5–6 h (short‑acting hypnotic). |
| Excretion | Renal (~40 %) and biliary; primarily metabolite‑free excretion. |
| Drug Interactions | Strong inhibitors/inducers of CYP3A4 alter exposure; cautioned with concurrent benzodiazepines, opioids, or CNS depressants. |
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Indications
- Short‑term treatment of primary insomnia (sleep onset and/or maintenance disturbances).
- Typically prescribed for ≤ 4 weeks due to risk of tolerance and rebound insomnia.
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Contraindications
| Category | Recommendation |
| Contraindicated | – Known hypersensitivity to zopiclone or imidazopyridine scaffold. – Severe hepatic impairment. |
| Warnings | – Pregnancy Category B; limited data – use only if benefit outweighs risk. – Breastfeeding: excretion in milk; avoid in nursing mothers. – Elderly (≥ 65 yrs) and those with renal impairment: start at lowest dose; monitor for increased sensitivity. – History of substance abuse or psychiatric disorders: risk of misuse, dependence. |
| Precautions | – Concomitant CNS depressants (opioids, alcohol): additive sedation. – Use cautiously with CYP3A4 inhibitors (ketoconazole, clarithromycin). |
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Dosing
| Population | Initial Dose | Titration | Max Daily Dose |
| Adults | 2.5 mg nightly before bedtime | May increase to 3.75 mg if needed (≥ 4 weeks) | 7.5 mg |
| Elderly | 2.5 mg nightly | Avoid titration; keep at lowest effective dose | 2.5 mg |
| Renal/Hepatic Impairment | 1.25 mg nightly (if hepatic issues) | Monitor closely | ≤ 2.5 mg |
| Pregnancy | Use only if therapeutic need > benefits | Follow obstetric guidance | —
• Route: Oral capsule; take swiftly with a glass of water (not with food to avoid delayed absorption).
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Adverse Effects
| Adverse Effect | Frequency | Notes |
| Somnolence / Sedation | Common | May impair daytime functioning. |
| Taste disturbance (dysgeusia) | Common | Often resolves within 1–2 weeks. |
| Dry mouth and blurred vision | Mild | Counsel patients to maintain hydration. |
| Headache and dizziness | Mild | May enhance fall risk in elderly. |
| Psychomotor impairment / sedation | Rare | Avoid driving/forklift until effect known. |
| Rebound insomnia | Moderate | Occurs when therapy discontinued abruptly. |
| Dependence & withdrawal | Low–moderate | Taper over 1–2 weeks if therapy extends >4 weeks. |
| Mood changes / anxiety | Rare | Monitor for emergence of psychiatric symptoms. |
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Monitoring
- Baseline: liver function tests; renal profile if indicated; assess psychiatric history.
- During therapy:
- Sleep diary to gauge efficacy and rebound.
- Cognitive assessments in elderly patients (Mini‑Cog).
- Observation for mood alterations or emergent anxiety.
- When adjusted: re-evaluate LFTs if dose exceeds 3.75 mg or if hepatic comorbidity.
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Clinical Pearls
- Rapid onset + short half‑life → ideal for “sleep‑onset insomnia,” but not for maintenance‑only problems where longer‑acting agents may be preferable.
- Mini‑dose strategy: 1.25‑2.5 mg works for many patients; higher doses rarely confer additional benefit and increase side‑effect odds.
- Non‑linear pharmacokinetics in hepatic disease: because of CYP3A4 reliance, even mild liver dysfunction can significantly raise plasma levels; use at or below 1.25 mg in Child‑Pugh B/C.
- Preference over benzodiazepines: zopiclone has minimal anxiolytic, anticonvulsant or euphoric effects, reducing abuse potential but still requires caution in at‑risk individuals.
- Tapering: to avoid rebound insomnia and withdrawal, reduce dose by 0.5 mg every 3–5 days if therapy >4 weeks.
- Dental practice: zopiclone induces dry mouth → increase post‑operative hydration.
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• Key Takeaway: Zopiclone provides a fast‑acting, short‑duration hypnotic with a favorable pharmacokinetic profile for brief insomnia treatment, but its use demands careful patient selection, vigilant monitoring, and judicious dosing to mitigate tolerance, dependence, and CNS adverse events.