L15: Sedative-Hypnotics, Barbiturates, and Benzodiazepines

This set of vocabulary flashcards covers the history, medical uses, safety profiles, and molecular mechanisms of sedative-hypnotic drugs, specifically barbiturates, benzodiazepines, and GHB, as well as the functions of the GABA system.

Sedative-hypnotics and anxiolytics

A diverse group of compounds that depress the CNS and behaviour, including alcohol, barbiturates, non-barbiturate hypnotics, and tranquilizers.

Barbituric acid

The foundation of all barbiturates, first synthesized by von Baeyer in 1864.

Barbital (1903) and phenobarbital (1912)

The first two barbiturate drugs to be marketed.

Pharmacokinetic factors of barbiturates

High lipid solubility allows them to reach the brain fast, but they are then redistributed to body fat stores, resulting in a brief duration of action.

Therapeutic Index

Determined by the ratio $\text{LD}<em>{50} / ext{ED}</em>{50}$; it is used to measure the safety margin of a drug.

Ultrashort-acting barbiturates

Barbiturates like Thiopental (Pentothal) and Methohexital (Brevital) with high lipid solubility, an onset of $10-20\,\text{s}$, and a duration of $20-30\,\text{min}$, used for intravenous anesthesia.

Long-acting barbiturates

Drugs such as Phenobarbital (Luminal) and Mephobarbital (Mebaral) with low lipid solubility, an onset of over $1\,\text{h}$, and a duration of $10-12\,\text{h}$, used for prolonged sedation and seizure control.

Barbiturate effects on sleep

Initially helpful for sleep induction, but repeated use leads to a reduction in both REM sleep and deep (slow-wave) sleep, making it harder to fall asleep.

Librium (1959) and Valium (1963)

The first benzodiazepines marketed to replace barbiturates for treating anxiety and insomnia.

Benzodiazepine Medical Uses

Anxiolytics, sedatives, anticonvulsants, treatment for alcohol withdrawal, and surgical sedation/amnesia.

GHB (gamma-hydroxybutyrate)

A $\text{GABA}$ analog and "club drug" that occurs naturally in the brain in small quantities and acts as an agonist at two types of GPCRs.

GABA (gamma-aminobutyric acid)

The most important inhibitory neurotransmitter in the adult vertebrate brain; it is synthesized from glutamate.

GAT-1, GAT-2, and GAT-3

Membrane $\text{GABA}$ transporters located on both neurons and glia.

GABAA receptor

An ionotropic ligand-gated channel that allows chloride ($Cl^-$) influx, leading to hyperpolarization (inhibition).

GABAB receptor

A metabotropic G-protein-coupled receptor; $\text{GHB}$ is a low-affinity agonist of this receptor.

Muscimol

An agonist for the $\text{GABA}_A$ receptor.

Bicuculline

An antagonist for the $\text{GABA}_A$ receptor.

Allosteric modulators

Drugs like barbiturates and benzodiazepines that do not bind to the same site as $\text{GABA}$ but enhance the chloride influx produced by $\text{GABA}$.

Diazepam effect on GABAA channels

Causes $\text{GABA}_A$ channels to open more frequently in the presence of $\text{GABA}$.

Phenobarbital effect on GABAA channels

Causes $\text{GABA}_A$ channels to stay open for longer durations.

alpha 1 (a1) containing GABAA receptors

Subtypes required for the sedative and amnesic effects of benzodiazepines.

alpha 2 (a2) containing GABAA receptors

Subtypes required for the anxiolytic effects of benzodiazepines, located primarily in the limbic system.