Drugs, Brain and Behaviour (15): Barbiturates & Benzodiazepines

Sedative-hypnotics

CNS depressant drugs that reduce neural activity and produce sedation and sleep.

Main sedative-hypnotic groups

Barbiturates, benzodiazepines, alcohol, non-barbiturate hypnotics, and GHB.

Dose-dependent effects

Increasing dose leads from sedation → hypnosis → anaesthesia → coma → death.

CNS depressants

Drugs that reduce central nervous system activity.

Additive effects

Combined use of depressants increases overall drug effect.

Cross-tolerance

Tolerance to one depressant reduces sensitivity to others.

Barbiturates

A class of sedative-hypnotic drugs with high overdose risk.

Barbituric acid

First synthesised in 1864, forming the basis of barbiturates.

Early barbiturate drugs

Barbital (1903) and phenobarbital (1912).

Historical uses of barbiturates

Sedation, sleep induction, anxiety reduction, anaesthesia, anticonvulsants.

Modern use of barbiturates

Greatly reduced due to safety concerns.

Barbiturate pharmacokinetics

High lipid solubility allows rapid brain entry.

Redistribution

Movement of drug from brain to fat tissue reduces duration of action.

Behavioural effects of barbiturates

Sedation, reduced anxiety, disinhibition, similar to alcohol.

Drug interaction effect

Barbiturates enhance effects of other depressants.

Reinforcing effects of barbiturates

Readily self-administered by animals.

Preference for rapid-acting drugs

Faster onset increases abuse potential.

Punishment resistance

Barbiturates increase behaviour even when punished.

Barbiturates and sleep

Initially help sleep but disrupt long-term sleep quality.

REM sleep effect

Barbiturates reduce REM sleep.

Slow-wave sleep effect

Reduced deep sleep.

Long-term sleep effect

Can worsen insomnia.

Barbiturate tolerance

Develops rapidly with repeated use.

Barbiturate withdrawal

Severe and can include seizures.

Therapeutic index of barbiturates

Low, meaning high overdose risk.

Barbiturate overdose

Historically a common cause of death.

Barbiturates in suicide

Frequently used due to high lethality.

Benzodiazepines (BZs)

Safer sedative-hypnotics developed to replace barbiturates.

Examples of benzodiazepines

Diazepam, Chlordiazepoxide, Alprazolam.

Medical uses of benzodiazepines

Anxiety, insomnia, seizures, alcohol withdrawal, sedation, muscle relaxation.

Advantages of benzodiazepines

Safer, less severe withdrawal, lower abuse potential than barbiturates.

Risk of benzodiazepines

Dangerous when combined with other depressants (e.g., alcohol).

Benzodiazepine pharmacokinetics

Differ mainly in duration of action.

Factors affecting duration

Metabolism and active metabolites.

Long-acting benzodiazepines

Remain in body longer due to multiple metabolic steps.

Benzodiazepine abuse

Lower than barbiturates but still present.

Self-administration of BZs

Harder to establish in animal models.

Benzodiazepine dependence

Can develop with repeated use.

Withdrawal symptoms (BZs)

Anxiety, sensory sensitivity, emotional disturbances.

Example misuse drug

Flunitrazepam used in drug-facilitated assault.

GHB (gamma-hydroxybutyrate)

A sedative-hypnotic similar to GABA.

GHB natural presence

Found in small amounts in the brain.

GHB effects

Relaxation, disinhibition, mild stimulation at low doses.

GHB risks

High doses cause coma and seizures.

GHB misuse

Associated with club use and drug-facilitated assault.

GHB mechanism

Acts on GHB receptors and GABA-B receptors.

GABA

Main inhibitory neurotransmitter in the brain.

Full name of GABA

Gamma-aminobutyric acid.

GABA-A receptor

Ionotropic receptor allowing Cl⁻ influx.

Effect of GABA-A activation

Hyperpolarisation and neuronal inhibition.

GABA-B receptor

Metabotropic receptor producing slower inhibitory effects.

GABA-A receptor structure

Made of 5 subunits with many subtypes.

Subunit variability

Different subtypes produce different behavioural effects.

Allosteric modulation

Drug binds to a different site than the natural ligand to enhance its effect.

Mechanism of barbiturates and benzodiazepines

Both enhance GABA-A receptor activity.

Binding difference

Barbiturates and benzodiazepines bind to different sites on GABA-A receptors.

Benzodiazepine mechanism

Increase frequency of Cl⁻ channel opening.

Effect of benzodiazepines

Enhanced inhibition and reduced anxiety.

Barbiturate mechanism

Increase duration of Cl⁻ channel opening.

Additional barbiturate effect

Can directly activate GABA-A receptors at high doses.

Result of barbiturate action

Stronger CNS depression.

Why barbiturates are dangerous

Direct activation leads to high overdose risk.

Why benzodiazepines are safer

Require GABA presence, limiting maximum effect.

GABA-A α1 subunit

Associated with sedation and amnesia.

GABA-A α2 subunit

Associated with anxiolytic effects.

Implication of receptor subtypes

Potential to develop drugs targeting anxiety without sedation.

Endogenous benzodiazepine-like compounds

Naturally occurring molecules that modulate GABA-A receptors.

Example endogenous ligands

Steroid metabolites such as progesterone derivatives.

Function of endogenous modulators

Regulate anxiety and stress responses.

Core mechanism of sedative-hypnotics

Enhancement of inhibitory GABA signalling.

Key difference (BZs vs barbiturates)

Frequency vs duration of Cl⁻ channel opening.

Clinical importance

Used for anxiety, sleep, seizures, and alcohol withdrawal.

Main risk of sedatives

Dangerous when combined with other CNS depressants.