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

Sedative-Hypnotics

CNS depressant drugs that reduce neural activity and produce sedation and sleep (e.g. Barbiturates, benzodiazepines, alcohol, non-barbiturate hypnotics, and GHB).

Dose-dependent Effects of Sedative-Hypnotics

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 CNS depressant historically used for:

• Sedation

• Anxiety reduction

• Anaesthesia

Has high overdose risk

History of Barbiturates

1864: Barbituric acid first synthesised, forming the basis of barbiturates.

1900s: Early barbiturate drugs: Barbital (1903) and phenobarbital (1912).

Modern Usage: Greatly reduced due to safety concerns.

Pharmacokinetics of Barbiturates

High lipid solubility allows rapid brain entry.

Redistribution

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

Barbiturates & Drug Interaction Effects

Barbiturates enhance effects of other depressants.

Barbiturates & Self-administration

Readily self-administered by animals → Reinforcing. Barbiturates are rapid-acting drugs, faster onset increases abuse potential.

Barbiturates & Punishment Resistance

Barbiturates increase behaviour even when punished.

Barbiturates and Sleep

Initially helps sleep but disrupts long-term sleep quality of:

• REM sleep

• deep sleep

• worsen insomnia.

Barbiturate Tolerance

Reduced drug effects requiring higher doses to achieve the same sedative/hypnotic effects. Develops rapidly with repeated use.

Barbiturate Withdrawal

Severe symptoms (e.g. seizures) resulting from quitting barbiturate use.

Therapeutic index of Barbiturates

Low → meaning high overdose risk.

Barbiturates & Overdose

Historically a common cause of death. Frequently used in suicides due to high lethality.

Benzodiazepines (BZs)

Safer sedative-hypnotics developed to replace barbiturates (e.g. Diazepam, Chlordiazepoxide, Alprazolam). Used for:

• Anxiety

• Insomnia

• Sedation

Advantages of Benzodiazepines

• Safer

• Less severe withdrawal

• Lower abuse potential than barbiturates.

Risk of Benzodiazepines

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

Benzodiazepines Pharmacokinetics

High lipid solubility allows rapid brain entry similar to barbiturates, but BZs have a longer duration

Factors affecting Duration of Drugs

• Metabolism

• Active Metabolites (compounds formed when the body metabolises drugs)

Benzodiazepines & Self-administration

BZs are NOT readily self-administered by animals

Benzodiazepines & Dependence

Where a person requires a substance to function normally and absence leads to withdrawal symptoms. Can develop with BZs with repeated use.

Benzodiazepines & Withdrawal

Severe symptoms resulting from quitting benzodiazepines use. Includes:

• Anxiety

• Sensory sensitivity

• Emotional disturbances

GHB (gamma-hydroxybutyrate)

A sedative-hypnotic similar to GABA. Found naturally in small amounts in the brain. Causes:

• Relaxation

• Disinhibition

• Mild stimulation

GHB Risks

High doses cause coma and seizures.

GHB Misuse

Associated with drug-facilitated assault (“date rape drug”).

GHB Mechanism

Acts on GHB receptors and GABA-B receptors to produce CNS depression by increasing inhibitory signalling.

GABA

Gamma-aminobutyric acid - Main inhibitory neurotransmitter in the brain.

GABA-A Receptor

Ionotropic receptor (made of 5 subunits with many subtypes) allows Cl⁻ influx. Activation leads to hyperpolarisation and neuronal inhibition.

GABA-B Receptor

Metabotropic receptor producing slower inhibitory effects.

GABA-A Receptor 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.

Receptor Binding & Barbiturates and Benzodiazepines

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

Benzodiazepines Mechanism

Increases frequency of Cl⁻ channel opening → Enhanced inhibition and reduced anxiety.

Barbiturates Mechanism

Increases duration of Cl⁻ channel opening → Stronger CNS depression.

Why are Barbiturates dangerous?

Can directly activate GABA-A receptor at high doses → leads to high overdose risk.

Why are Benzodiazepines safer?

Requires GABA to be present for channel opening, limiting maximum effect.

GABA-A Subunits & effects

GABA-A α1 subunit: Associated with sedation and amnesia.

GABA-A α2 subunit: Associated with anxiolytic effects.

→ Implies potential to develop drugs targeting anxiety without sedation.

Endogenous Benzodiazepines-like Compounds

Naturally occurring molecules that modulate GABA-A receptors → Regulates anxiety and stress responses (e.g. Steroid metabolites such as progesterone derivatives).

Core mechanism of sedative-hypnotics

Enhancement of inhibitory GABA signalling

Main risk of Sedatives

Dangerous when combined with other CNS depressants.