Sedatives and Hypnotics

Sedatives and Hypnotics are drugs that calm the CNS, with sedatives promoting relaxation and hypnotics inducing sleep.

Definition of Sedatives and Hypnotics:

• Sedatives: Drugs that reduce anxiety and exert a calming effect without inducing sleep at low doses.
• Hypnotics: Drugs that induce and maintain sleep at higher doses.

The same drug can act as both a sedative and a hypnotic depending on dose.

Mechanism of Action

• Most act by potentiating GABA-A receptors → increased Cl⁻ influx → neuronal hyperpolarization → CNS depression
• BZDs: Increase frequency of Cl⁻ channel opening
• Barbiturates: Increase duration of Cl⁻ channel opening
• Z-drugs: Selectively bind to BZ1 site on GABA-A receptor

Classification of Sedative-Hypnotics

1. Benzodiazepines (BZDs)

   • Examples:
     • Diazepam, Lorazepam, Midazolam, Alprazolam, Temazepam, Triazolam
   • Mechanism:
     • They bind to a specific site on the GABA-A receptor (a chloride ion channel).
     • This increases the frequency of the chloride channel opening when GABA (an inhibitory neurotransmitter) binds.
     • More Cl⁻ ions enter neurons → the inside becomes more negative → hyperpolarization → neurons are less likely to fire → sedation, muscle relaxation, reduced anxiety.
   • Clinical Uses:
     • Anxiolytic (anti-anxiety) – e.g., Alprazolam for panic disorder
     • Hypnotic (sleep aid) – e.g., Temazepam, Triazolam
     • Muscle relaxant – e.g., Diazepam for spasms
     • Anticonvulsant – e.g., Lorazepam in status epilepticus
     • Pre-anesthetic/sedation – e.g., Midazolam before surgery
   • Notes:
     • Compared to barbiturates, they are safer because they have a “ceiling effect”—after a certain dose, increasing the amount doesn’t cause much more CNS depression (less risk of fatal overdose when used alone).

2. Non-Benzodiazepine Hypnotics (“Z-drugs”)

   • Examples:
     • Zolpidem, Zaleplon, Eszopiclone
   • Mechanism:
     • They selectively bind to the BZ1 receptor subtype on the GABA-A complex (not all subtypes like BZDs do).
     • This results in sedative effects but minimal anxiolytic or muscle relaxant
   • Clinical Use:
     • Primarily used for insomnia—especially difficulty falling asleep or staying asleep.
   • Advantages:
     • Short half-lives → less hangover effect in the morning
     • Lower risk of dependence, abuse, and cognitive impairment
   • Limitations:
     • Not effective for anxiety, seizures, or muscle spasms
     • Can still cause sleepwalking or odd behaviors (especially with Zolpidem)

3. Barbiturates

   • Examples:
     • Phenobarbital, Thiopentone, Secobarbital
   • Mechanism:
     • Bind to GABA-A receptors and increase the duration that the Cl⁻ channel stays open
     • At high doses, can mimic GABA directly → much more potent CNS depression
   • Uses:
     • Older drugs once widely used for sleep and seizures
     • Now mostly limited:
       • Phenobarbital: seizures
       • Thiopentone: rapid induction of anesthesia
   • Risks:
     • High toxicity: narrow therapeutic index
     • Can cause respiratory depression, coma, death (especially in overdose)
     • High potential for dependence and withdrawal

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