Sedative-Hypnotics: Barbiturates and Benzodiazepines

Flashcards covering the pharmacology, history, medical uses, and molecular mechanisms of sedative-hypnotics including barbiturates, benzodiazepines, and GHB.

Sedative-hypnotics (Anxiolytics)

A diverse group of compounds that depress the central nervous system (CNS) and behavior, including alcohol, barbiturates, and tranquilizers.

von Baeyer (1864)

The chemist who first made barbituric acid, which serves as the foundation of all barbiturates.

Barbital (1903)

The first barbiturate drug to be marketed.

Redistribution

The pharmacokinetic process where high lipid solubility allows drugs to reach the brain fast, followed by movement into body fat stores, resulting in a brief duration of action.

Barbiturate sleep disruption

With repeated use, barbiturates cause a reduction in both REM sleep and deep (slow-wave) sleep, and make it harder to fall asleep.

Therapeutic index

Calculated as $LD_{50} / ED_{50}$; it is used to measure safety margins, which are much higher for benzodiazepines than for barbiturates.

Librium (1959)

The first benzodiazepine drug to reach the market.

Valium (1963)

A widely used benzodiazepine marketed shortly after Librium.

Flunitrazepam (Rohypnol)

A rapid-onset benzodiazepine sometimes used in date rape cases.

GHB (gamma-hydroxybutyrate)

Synthesized as a GABA analog that crosses the blood-brain barrier; it acts as a popular club drug with subjective effects resembling alcohol.

GABA (gamma-aminobutyric acid)

The most important inhibitory neurotransmitter in the adult vertebrate brain, synthesized from glutamate.

vGAT

The vesicular GABA (and glycine) transporter.

GAT-1, 2, 3

Membrane GABA transporters found on both neurons and glia.

$GABA_A$ receptor

An ionotropic (ligand-gated chloride channel) receptor consisting of 5 subunits (typically 2 $\alpha$, 2 $\beta$, and a $\gamma$ or $\delta$).

$GABA_B$ receptor

A metabotropic (G-protein-coupled) receptor.

Muscimol

An agonist for the $GABA_A$ receptor.

Bicuculline

An antagonist for the $GABA_A$ receptor.

Allosteric modulators

Drugs like barbiturates and benzodiazepines that do not bind to the same site as GABA but enhance the ability of GABA to cause chloride influx.

Diazepam effect on $GABA_A$

In the presence of GABA, this drug causes $GABA_A$ channels to open more frequently.

Phenobarbital effect on $GABA_A$

In the presence of GABA, this drug causes $GABA_A$ channels to stay open for longer.

$\alpha_1$-containing receptors

Subtypes of the $GABA_A$ receptor required for the sedative and amnesic effects of benzodiazepines.

$\alpha_2$-containing receptors

Subtypes of the $GABA_A$ receptor required for the anxiolytic effects of benzodiazepines.

Disinhibition

The process by which benzodiazepines increase the activity of dopaminergic neurons by inhibiting the inhibitory interneurons that normally restrict them.