MOA of Barbiturates (Phenobarbital and Thiopental)

Phenobarbital is a barbiturate that is effective in the treatment of generalized tonic-clonic

and partial seizures. The mechanism of action for phenobarbital is related to the elevation of
seizure threshold by interacting with y-aminobutyric acid A (GABAA) postsynaptic receptors
which potentiates synaptic inhibition.
GABAA receptor is a hetero-oligomeric glycoprotein which consists of five or more
membrane-spanning subunits. Multiple forms of alpha, beta and gamma subunits are arranged in
different pentameric combinations so that GABAA receptors exhibit molecular heterogeneity. The
neurotransmitter GABA appears to interact at two sites between alpha and beta subunits (Figure )
trigerring chloride channel opening with resulting membrane hyperpolarization. Barbiturates
binds at multiple isoforms of the receptor allosterically increasing the duration of the opening of
the chloride ion transporter wherein chloride anion enters the neuron causing hyperpolarization.
This will then decrease the neuronal activity inducing the loss of the righting reflex.

Figure ( ). A model of the GABAA receptor-chloride ion channel macromolecular complex.

GABA is the major inhibitory neurotransmitter in the Central Nervous System which
binds to GABA receptors. Barbiturates (Phenobarbital and Thiopental) facilitate the actions of

GABA at multiple sites in the CNS by increasing the duration of the GABA-gated chloride
channel openings. At higher dose of barbiturates, they may also be GABA mimetic which
directly activates chloride channels. Barbiturates are less selective in their actions than other
sedative-hypnotic-anxiolytic drugs like benzodiazepines, because they also depress the actions of
the excitatory neurotransmitter glutamic acid via binding to the AMPA receptor and at higher
concentration also block Sodium channels. Barbiturates also exert nonsynaptic mebrane effects
in parallel with their effects on GABA and glutamate neurotransmisson. The findings that
barbiturates potentiate inhibitory GABAA receptors and inhibit excitatory AMPA receptors can
explain the CNS-depressant effects of these agents. The effects of such drugs range from
sedation and relief of anxiety (anxiolysis, through hypnosis (facilitation of sleep), to anesthesia
and coma.
Uses of barbiturates as a drug includes the following:

Sedation these agents have largely been replaced by more modern and safer agents like

benzodiazepines in this area.

Sleep induction or hypnosis in short term insomnia, barbiturates may be effective.
This is because they tend to lose their effectiveness in sleep induction and maintenance

after 2 weeks of use.

Before surgery as a preanesthetic agent sedation is given prior to surgery to allay
anxiety and to ease the process of induction of general anesthesia. This is also an area

where benzodiazepines have replaced barbiturates.

Induction of general anesthesia Thiopentone or pentothal is routinely used as an

injectable induction agent in general anesthesia.

Treatment of seizures - treatment of partial and generalized tonic-clonic and cortical
focal seizures could still utilize barbiturates including mephobarbital, Phenobarbital.

Acute convulsions acute onset convulsions including status epilepticus, eclampsia

during pregnancy, meningitis, tetanus and toxic reactions to strychnine or local
anesthetics, convulsions during cholera etc. are indications for use of barbiturates.