Sedative–Hypnotics & Anxiolytics

• GABA_A Ligand‑gated chloride channel complex
• Pentameric structure: α, β, γ, ρ, δ subunits (most common: 2α, 2β, 1γ)
• BZ binding site located at α‑γ interface (distinct from GABA site)
• BZ₁ (α1) → sedation, amnesia, ataxia
• BZ₂ (α2, α3, α5) → anxiolytic, myorelaxant, cognitive effects
• Mechanism Positive allosteric modulation
• Increases frequency of Cl⁻ channel opening (not duration)
• Requires GABA to be present — no direct GABA‑mimetic effect
• Result: enhanced inhibitory postsynaptic potential (IPSP) → neuronal hyperpolarization
• Flumazenil: competitive antagonist at BZ site
• Reverses BZ‑induced CNS depression (not barbiturate or ethanol)
• Used in BZ overdose and post‑anesthesia

• GABA_A Bind to distinct site (different from BZ site)
• Prolong duration of Cl⁻ channel opening (not frequency)
• At higher doses: direct GABA‑mimetic action (can open channel without GABA)
• Also inhibit complex I of mitochondrial electron transport chain
• This contributes to CNS depression and toxicity
• No ceiling effect → dose‑dependent depression up to anesthesia, coma, respiratory arrest
• Pharmacokinetics:
• Hepatic metabolism, often to active metabolites
• Potent inducers of cytochrome P450 (CYP3A4, 2C9, etc.)
• Contraindicated in porphyria (induce ALA synthase)
• Clinical use: phenobarbital for seizures (still used)
• Cross‑tolerance with ethanol and BZs (due to shared GABA potentiation)

• PK Most BZs undergo hepatic oxidation to active metabolites
• Exception: oxazepam, temazepam, lorazepam (direct glucuronidation, no active metabolites)
• Lipophilic → distribute widely; redistribution contributes to short duration
• Acute anxiety: BZs are first‑line (rapid onset)
• Chronic anxiety: SSRIs/SNRIs preferred for maintenance (BZs not preventive)

• Tolerance Develops to sedative, hypnotic, anticonvulsant effects
• Less tolerance to anxiolytic effect
• Cross‑tolerance: BZs ↔ barbiturates ↔ ethanol (GABA_A‑mediated)
• Dependence Psychological and physical
• Abuse potential: BZ < ethanol < barbiturates
• BZ withdrawal syndrome:
• Rebound insomnia, anxiety, agitation
• Seizures (especially if high dose or used as anticonvulsant)
• Barbiturate/ethanol withdrawal:
• Anxiety, tremor, life‑threatening seizures, delirium tremens
• Management: supportive care + long‑acting BZ (e.g., diazepam)

• Zolpidem / Zaleplon Selective BZ₁ (α1) agonists
• Sedative effect with less cognitive (BZ₂) impairment
• Used for insomnia (sleep onset)
• Overdose reversed by flumazenil
• Lower tolerance/abuse liability than BZs, but sleepwalking reported
• Buspirone 5‑HT_1A partial agonist (no GABA effect)
• Indicated for generalized anxiety disorder (GAD)
• Non‑sedating, no abuse potential
• Therapeutic effect delayed 1–2 weeks
• Suvorexant Orexin receptor antagonist
• Blocks orexin (promotes wakefulness) → used for insomnia
• Side effect: somnolence (dose‑dependent)

• Drug interactions Additive CNS depression with anesthetics, antihistamines, opioids, β‑blockers
• Barbiturates accelerate metabolism of oral contraceptives, warfarin, phenytoin, carbamazepine
• BZs: less significant enzyme induction; interactions mainly pharmacodynamic