Pharmacology of the central GABA-ergic system

Question 1

Anxiolytic effect

Answer 1

• reduction of anxiety without influencing motor or

mental functions

Question 2

Sedative effect

Answer 2

• suppression of responsiveness to a constant level of
stimulation with decreased spontaneous activity and
ideation

Question 3

Hypnotic effect

Answer 3

• producing drowsiness, promoting the onset and
maintenance of a state of sleep that as far as
possible resembles the natural sleep state

Question 4

GABAergic neurotransmission

Answer 4

• GABA – most important inhibitory transmitter in the brain
• Synthesis: from glutamate by the enzyme Glutamic Acid Decarboxylase
• Termination of action: uptake (re-uptake or glia).
• Breakdown: GABA-transaminase.
• glutamine-glutamate/GABA cycle: transfer of glutamine from astrocytes to neurons and neurotransmitter glutamate or GABA from neurons to astrocytes

Question 5

antiepileptic effect on GABAergic transmission

Answer 5

• some antiepileptics enhance the GABAergic transmission at the presynaptic site:
vigabatrin, valproate
GABA-transaminase inhibition;
tiagabin – GABA-uptake inhibition

Question 6

GABA receptors

Answer 6

• GABA-A (ionotropic)

* GABA-B (G-protein-coupled)

Question 7

GABA-A receptor

Answer 7

•GABA-A receptors are heteropentameric ligand-gated ion channels that permit the influx of Cl- ions to decrease membrane excitability. GABA-A receptors mediate the majority of fast synaptic inhibition. GABA-A
receptors are extremely important pharmacological targets. The most sedative-hypnotics act at this receptor complex.
• Muscimol is an agonist, bicuculline is an antagonist at the GABA binding site.
• Picrotoxin is a channel-blocker (or a non-competitive antagonist).
• Benzodiazepines and barbiturates are positive allosteric modulators.

Question 8

GABA-B receptor

Answer 8

• Metabotropic GABAB receptors are expressed on both the presynaptic and postsynaptic terminals where they
inhibit neurotransmitter release and induce cell membrane hyperpolarization. GABA-B-agonist: baclofen
(centrally acting skeletal muscle relaxant
used in skeletal muscle spasticity).

Question 9

modulating positively the GABAergic neurotransmission can cause the following actions in increasing doses

Answer 9

• anxiolytic action (unfortunately not fully distinguisable from sedation – lowest dose)
• hypnotic action (moderate dose)
• general anesthesia (still higher dose)
• coma and death (toxic dose)
  There is an additive synergism among the
  GABAergic or other sedatives and ethanol.

Question 10

Possible additional actions of GABAergic sedative-hypnotics (not obligatory):

Answer 10

• antiepileptic action
• skeletal muscle relaxant action
• amnesia

Question 11

GABA-A subunit composition: functional properties

Answer 11

• GABA- A-receptors with α1 -subunit – sedation, hypnotic effect E.g.; Z-hypnotics (zopiclone, zolpidem, zaleplon) - preferential affinity to binding sites at this receptor subtype.

• GABA-A-receptors with α2-subunit – anxiolytic effect
Anxiolytic effects without sedation.

• GABA-A-receptors with α5-subunit (in Hippocampus) - partial inverse agonists at the BDZ binding site: treatment of cognitive deficit ?

Question 12

Tranquillizers in the XIXth century

Answer 12

• chloral hydrate (synthesis 1832, used since 1869, the first synthetic hypnotic)

Question 13

The barbiturates

Answer 13

• barbituric acid: synthesized by Adolph von Baeyer 1864
• 1903 Emil Fischer, Joseph von Mering – the first
barbiturates in therapy: diethylbarbituric acid (Veronal)
1912 – Phenobarbital

Question 14

Mechanism of action of barbiturates

Answer 14

• They facilitate the actions of GABA by increasing the duration of the GABA-gated channel openings.
• At high concentrations they may activate directly the chloride channels.
• They might have further non-selective actions (depression of excitatory neurotransmission, nonsynaptic membrane effects).

This mechanism of action explains their ability to induce full surgical anesthesia and their more pronounced central depressant effects (low margin of safety).

Question 15

Long-acting barbiturates

Answer 15

• phenobarbital: old-fashioned sedative, hypnotic (not used for these indications).

• still used as an antiepileptic drug

Question 16

Medium and short-acting barbiturates

Answer 16

• cyclobarbital, amobarbital

- old-fashioned hypnotics

Question 17

Ultra-short-acting barbiturates

Answer 17

• thiopental, methohexital, hexobarbital
- important intravenous anesthetics
- the most important reason for their ultrashort duration of
action is the redistribution from the brain into other tissues

Question 18

Disadvantages of barbiturates

as sedative-hypnotics

Answer 18

• Low safety margin (intoxication is dangerous)
• No antagonist
• Psychologic and physical dependence, tolerance
• Enzyme induction, drug interactions

Question 19

Other sedative-hynotics in the barbiturate age

Answer 19

- chlomethiazole (1938)
• bromisoval, carbromal (30’s)
• chlorobutanol
• methyprylone
• ethchlorvynol
• glutethimide (1954)
• methaqualone (1955 – by product of malaria research)

Question 20

The monster drug: thalidomid

Answer 20

• synthesized in 1954 in an antibiotic research program
• no antibiotic effect, but seemed to be extremely safe in animals
• searching for therapeutic effect – free samples are distributed for doctors in Germany
• patients experience sedative and hypnotic effect
• marketed in 1957 in Germany (and in 46 countries in the world) as a sedative/hypnotic as over-the-counter drug, especially advised for pregnant woman because of „unusual safety”
• the mostly used sedative-hypnotic in Germany in 1961
• withdrawn in 1961 because of teratogenic effect