Sedatives and Hypnotics

• Sedation → calming effect without sleep

• Hypnosis → induction and maintenance of sleep

• Anxiolysis → reduction of anxiety

All classical sedative-hypnotics primarily enhance the action of GABA (Gamma Amino Butyric Acid), the main inhibitory neurotransmitter in the brain.

Neurophysiology Behind Sedation and Sleep

Normal sleep is regulated by:

• Reticular activating system
• Hypothalamus
• Suprachiasmatic nucleus
• GABAergic neurons

Sleep Architecture

Sleep consists of:

NREM (75–80%)

• Stage 1 → light sleep
• Stage 2 → sleep spindles
• Stage 3 → deep restorative sleep

REM (20–25%)

• Dream sleep
• Muscle atonia
• Memory consolidation

Important:
Benzodiazepines decrease REM sleep slightly but less than barbiturates.

Classification of Sedative-Hypnotics

A. Benzodiazepines (Most Common)

Short Acting

• Midazolam
• Triazolam

Intermediate Acting

• Lorazepam
• Alprazolam

Long Acting

• Diazepam
• Clonazepam

B. Barbiturates (Older Drugs)

Ultra Short Acting

• Thiopental (IV anesthesia)

Long Acting

• Phenobarbital (epilepsy)

C. Non-Benzodiazepine Hypnotics (Z-Drugs)

• Zolpidem
• Zopiclone
• Eszopiclone

Selective for sleep induction.

D. Melatonin Receptor Agonists

• Ramelteon
  Acts on MT1 & MT2 receptors.

Mechanism of Action

 

Benzodiazepines

• Bind to benzodiazepine site on GABA-A receptor
• Increase frequency of chloride channel opening
• Require presence of GABA (cannot activate alone)

Result:
⬇ Neuronal firing
⬇ Anxiety
⬇ Muscle tone
⬇ Seizure activity

Barbiturates

• Increase duration of chloride channel opening
• At high doses → directly open channel without GABA
• Narrow therapeutic index

High overdose risk.

Z-Drugs

• Selectively bind α1 subunit of GABA-A receptor
• Mainly produce hypnotic effect
• Minimal muscle relaxant effect

Pharmacokinetics

Absorption

• Well absorbed orally
• Highly lipid soluble

Distribution

• Cross blood-brain barrier rapidly
• Cross placenta
• Present in breast milk

Metabolism

• Liver metabolism (CYP450 enzymes)
• Diazepam forms active metabolites
• Lorazepam does NOT form active metabolites

Elimination

• Renal excretion

Elderly patients require dose reduction.

Therapeutic Uses

1. Anxiety Disorders

• Generalized anxiety disorder
• Panic disorder

2. Insomnia

• Short-term use recommended (2–4 weeks)

3. Pre-Anesthetic Medication

• Midazolam causes anterograde amnesia

4. Epilepsy

• Diazepam (status epilepticus)
• Clonazepam (absence seizures)

5. Alcohol Withdrawal

• Prevent delirium tremens

6. Muscle Spasm

• Spinal cord injury
• Cerebral palsy

Adverse Effects

CNS Effects

• Drowsiness
• Impaired coordination
• Confusion (elderly)
• Anterograde amnesia

Respiratory Depression

• Especially with alcohol
• More severe with barbiturates

Tolerance

• Due to receptor downregulation
• Dose escalation required

Dependence

• Physical and psychological

Withdrawal Symptoms

• Anxiety
• Tremors
• Insomnia
• Seizures (life threatening)

Drug Interactions

• Alcohol → severe respiratory depression
• Opioids → fatal combination
• CYP inhibitors → increase benzodiazepine levels

Overdose Management

Benzodiazepine Overdose

• Usually safe alone
• Flumazenil used cautiously

Barbiturate Overdose

• Severe respiratory depression
• No specific antidote
• Supportive care + ventilation

Special Populations

Elderly

• Increased fall risk
• Confusion

Pregnancy

• Risk of fetal CNS depression

Liver Disease

• Prefer Lorazepam (no active metabolites)

Summary

Sedatives and hypnotics act primarily through GABA-A receptor modulation to reduce CNS excitability. Benzodiazepines are safer and widely used, whereas barbiturates are limited due to overdose risk. Long-term use requires caution because of tolerance, dependence, and withdrawal risk.