Sedative-Hypnotics

Introduction & Classification - Sleepy Science Sorted

• Sedatives: ↓CNS activity, reduce anxiety, exert calming effect.
• Hypnotics: Induce drowsiness, facilitate onset & maintenance of sleep.
• Dose-dependent effects: Sedation → Hypnosis → Anesthesia → Coma.
• Sleep Physiology: NREM (restorative), REM (dreams). GABA (major inhibitory NT).
• Classification:
  • Benzodiazepines (BZDs): Diazepam, Lorazepam. (Safer profile).
  • Barbiturates: Phenobarbital. (Enzyme inducers, ⚠️ High risk).
  • Non-BZDs (Z-drugs): Zolpidem, Zaleplon. (Act on BZ1/ω1).
  • Melatonin Agonists: Ramelteon. (No abuse potential).
  • Orexin Antagonists: Suvorexant. (Targets wakefulness).

⭐ BZDs increase frequency of Cl- channel opening; Barbiturates increase duration of opening and can directly activate Cl- channels at high doses.

Benzodiazepines - Chill Pills Unpacked

• Mechanism: Bind BZD site on GABA-A receptor → ↑ frequency Cl⁻ channel opening → potentiate GABA. 📌 "Ben likes Frequent Clubs".
• Effects: Anxiolytic, sedative, hypnotic, anticonvulsant, muscle relaxant, anterograde amnesia.
• Key BZDs:

  Drug	t½ (hrs)	Metabolism	Primary Uses
  Diazepam	20-100	CYP P450 (active met)	Anxiety, status epilepticus, muscle spasm
  Lorazepam	10-20	Glucuronidation	Anxiety, seizures, pre-anesthetic
  Oxazepam	5-15	Glucuronidation	Anxiety (safer: elderly, liver disease)
  Midazolam	1.5-3.5	CYP P450	Sedation, anesthesia induction

• Adverse Effects: Drowsiness, ataxia, dependence, withdrawal, respiratory depression (↑ with alcohol).
• Antidote: Flumazenil.

⭐ Lorazepam, Oxazepam, Temazepam (📌 LOT) bypass Phase I metabolism (direct glucuronidation); safer in elderly/liver disease.

Barbiturates - Old School Knockouts

• Mechanism: Bind GABA-A receptor, ↑ duration of $Cl^-$ channel opening. 📌 Barbi-DURATES ↑ DURATion.
• Types (Duration of Action):
  • Ultra-short: Thiopental (IV anesthesia induction).
  • Short/Intermediate: Pentobarbital, Secobarbital (insomnia - largely obsolete).
  • Long: Phenobarbital (anticonvulsant, neonatal jaundice).
• Adverse Effects: Severe CNS/respiratory depression, high dependence/tolerance, potent CYP450 enzyme induction (drug interactions), paradoxical excitement.
• ⚠️ No specific antidote; supportive care crucial.

⭐ Contraindicated in acute intermittent porphyria (AIP) due to induction of ALA synthase enzyme.

Non-BZDs & Novel Agents - Zzzs & Beyond

• Z-Drugs: Selective BZ1 (ω1) receptor agonists on GABA-A. 📌 "Zzz-drugs help you catch Zzzs selectively."

  Drug	Onset	Duration	Key Notes
  Zolpidem	Rapid	Short (2-3h)	Sleep onset/maintenance; less hangover, amnesia risk
  Zaleplon	Very Rapid	Ultra-short (~1h)	For sleep initiation; minimal next-day sedation
  Eszopiclone	Rapid	Int. (~6h)	For sleep onset/maintenance; common metallic taste

• Ramelteon: Melatonin MT1/MT2 agonist. No dependence/abuse potential. For sleep-onset insomnia.
• Suvorexant: Dual Orexin Receptor Antagonist (DORA). Blocks wakefulness signals.

⭐ Z-drugs' BZ1 selectivity results in fewer anxiolytic, muscle relaxant, and anticonvulsant effects compared to traditional benzodiazepines.

Clinical Use & Caveats - Dosing Do's & Don'ts

• Uses: Insomnia (short-term), anxiety, seizures, anesthesia.
• Dosing:
  • Do: Lowest effective dose, shortest duration. Gradual taper.
  • Don't: Abrupt stop (withdrawal risk). Avoid in elderly (↑ falls, confusion) & pregnancy. No alcohol.
• Caveats:
  • Tolerance, dependence, withdrawal (can be severe).
  • Respiratory depression (additive with opioids/alcohol).
  • Anterograde amnesia (BZD).
  • 📌 "Z-Z-Z" drugs for sleep: Zolpidem, Zaleplon, EsZopiclone - less dependence than BZDs.

⭐ Flumazenil is the antidote for benzodiazepine overdose; it competitively antagonizes BZD binding at GABA-A receptors.

High‑Yield Points - ⚡ Biggest Takeaways

• Benzodiazepines: Potentiate GABA-A (↑ frequency of Cl⁻ channel opening). Antidote: Flumazenil for overdose.
• Barbiturates: Potentiate GABA-A (↑ duration of Cl⁻ channel opening), are strong enzyme inducers, no specific antidote.
• Z-drugs (Zolpidem, Zaleplon): Selective for α1-GABA-A receptors, treat insomnia, generally lower dependence risk.
• Buspirone: 5-HT1A partial agonist for chronic anxiety; non-sedating, slow onset of action.
• Ramelteon: Melatonin MT1/MT2 receptor agonist for sleep-onset insomnia; non-GABAergic mechanism.
• Suvorexant: Orexin receptor antagonist, promotes sleep by blocking wakefulness signals.