GABA + GABA RECEPTORS: BENZODIAZEPINES:

à GABA (𝛾-aminobutyric acid) è an amino acid à GABA has affinity for GABA A receptors è binds
- inhibitory neurotransmitter in brain. to a site located between 𝛼 and 𝛽 subunits è
- Hyperpolarises neurons è decreased probability of it agonist
firing an action potential à BZDs have affinity for GABA-A receptors è bind
- Expressed by ~ 20% of neurons in the brain. to a site between 𝛼 and 𝛾2 subunits
- Exerts its action via 2 distinct receptors: à BZDs no agonist activity, no effect on their own
and enhance effects of GABA that is bound to
1. GABA-A è ion channel selectively permeable to Cl- receptor
ions à an allosteric modulator, can be a positive (P) or
Ø Composed of 5 proteins (subunits) (N) negative (A) allosteric (M) modulator
Ø 18 different known subunits (α1-6; β1-3; γ1-3; δ; ε; θ) à BZDs are PAMs, increase frequency of channel
Ø Allows for diversity opening events
Ø Subunit combinations determine ANATOMICAL
à Only GABA-A receptors composed of 𝛼1, 𝛼2,𝛼3
LOCATION, PHYSIOLOGY and
or 𝛼5 subunits are sensitive to the benzodiazepines
PHARMACOLOGY of the receptor subtype
Ø Diversifies GABA function + pharmacology à Receptors composed of 𝛼4 and 𝛼6 insensitive to
throughout brain BZDs
Ø Alpha 5: sensorimotor gating, cognitive impairment, à Benzodiazepines with affinity for GABA-A
myorelaxation receptors composed of:
Ø Alpha 1: sedation, addiction anterograde amnesia, - 𝛼2 and/or 𝛼3 subunits induce anxiolytic and
anticonvulsant activity, premature cortical plasticity calming effects
Ø Alpha 2: anxiolysis, antihyperalgesia, antidepression, - 𝛼1 and 𝛼5 subunits induce sedation, hypnosis
cognitive impairment in schizophrenia, (at higher doses) and ataxia
myorelaxation 𝛼1, 𝛼2,𝛼3 or 𝛼5 subunits anticonvulsant activity
Ø Alpha 3: sensorimotor gating, suppression of thalmic à currently no subunit-specific BZD available è all
oscillation, myorelaxation, antihyperalgesia will have mixed actions and therefore unwanted
effects
2. GABA-B è metabotropic è 2nd messenger cascade
MIDAZOLAM
results in the opening of potassium channels è
à Convulsions
hyperpolarisation
- Status epilepticus
DIAZEPAM CLONAZEPAM - Febrile convulsions
à All forms of epilepsy - Convulsions in palliative care
à Muscle spasm
à Sedation
à Convulsions
- Conscious sedation for procedures
- Status epilepticus ALPRAZOLAM
- Sedative in combined anaesthesia
- Febrile convulsions à Short-term use in
- Sedation of patient receiving intensive care
- Convulsions due to anxiety
poisoning à Adjunct to antipsychotic for confusion and
à Anxiety restlessness in palliative care
Short-term
- Severe acute anxiety à Memory impairments, reduced alertness and confusion
- Control of acute à Interact with other CNS depressant drugs (alcohol, opiates) and
panic attacks antihypertensive drugs è depress the respiratory and cardiovascular centres in
à Acute alcohol withdrawal the brainstem è fatal.
à Uncharacteristic behaviours aggressive and violent acts è suppresses cortical
LORAZEPAM inhibition of limbic areas of the brain normally modulates social behaviour or
à Anxiety conventions
- Short-term use in Long-term
anxiety
à Apathy è ‘emotional anaesthesia’.
- Short-term use in
à Aggravate depressiveè provoke suicide
insomnia associated
with anxiety à Dependence è patients display a physical withdrawal syndrome è rebound
- Acute panic attacks anxiety, insomnia, nausea, and cognitive, perceptual and mood changes è
à Anaesthesia premedication patients have to keep on taking them.
à Convulsions à BDZs have anticonvulsant propertiesè sudden withdrawal è epileptic-like
- Status epilepticus seizures è withdraw gradually over a number of weeks or months.
- Febrile convulsions OVERDOSE
- Convulsions caused by Ø Flumazenil è competitive BDZ antagonist, non-selective for α1, α2, α3 or
poisoning α5-containing GABA-A receptors.
 Non-benzodiazepines allosteric modulators of GABA-A receptors
Benzodiazepine antagonist
à Known as “Z” drugs
à Zolpidem + Zopiclone
FLUMAZENIL
Ø Binding site is near α1 and γ2 subunits, but different to
à Reversal of sedative effects of
that of benzodiazepines
benzodiazepines
Ø Zolpidem has high binding affinity to α1-GABA-A
Ø in anaesthesia and clinical procedures
receptors, with much lower affinity for α2/3. No affinity
Ø in intensive care
Ø in overdose for α5
Ø Zopiclone has higher affinity for α1 and α5-GABA-A
receptors, but still some modulation for α2/3.
MIXED GABA-A receptor Allosteric
PHARMACOLOGICAL EFFECTS
modulation AND Agonism
q Strong hypnotic (sedation), but weak anxiolytic,
myorelaxant, and anticonvulsant properties.
Barbiturates
CLINICAL INDICATIONS
à Thiopental
Insomnia (short-term use)
à Phenobarbital
Ø Barbiturates bind to at multiple sites on
different subunits that are different to MIXED GABA-A receptor Allosteric modulation AND Agonism
the GABA and benzodiazepine binding
sites
Etomidate
Ø At LOW concentrations, Barbiturates
Binding site is on β2 and β3 subunits of the GABA-A receptor.
facilitate the actions of GABA
AT CLINICAL DOSES
à Act as allosteric modulators by increasing
à acts as a positive allosteric modulators
the DURATION of the GABA-gated chloride
à Enhances the effects of endogenous GABA in inducing both
channel openings.
synaptic and extrasynaptic (tonic) currents
à Different to benzodiazepines that increase
AT SUPRA-CLINICAL DOSES
the FREQUENCY of channel openings
à Directly activates GABA-Receptors
à At HIGH concentrations, barbiturates
à Acts as an agonist
- directly activate GABA-A receptors
CLINICAL INDICATIONS
- Function as direct agonists
- Also depress the actions of glutamate à intravenous induction of general anaesthesia
by binding to the AMPA receptor.
à Multiplicity of sites of action of Propofol
barbiturates may be the basis for their ability Precise mechanism of action unclear
to induce full surgical anaesthesia rather than q Binding site is on γ, α, β subunits of the GABA-A receptor
just sedation q Also inhibits sodium ion channels
à Low margin of safety compared with AT CLINICAL DOSES
benzodiazepines and the newer hypnotics à acts as a positive allosteric modulators by enhancing the effects
CLINICAL INDICATIONS of endogenous GABA
q Status epilepticus AT SUPRA-CLINICAL DOSES
q Induction of anaesthesia à Acts as an agonist and directly activates GABA-Receptors
q Reduction of raised intracranial CLINICAL INDICATIONS
pressure if ventilation controlled à Intravenous induction of general anaesthesia

GABA-B receptor agonism

BACLOFEN
Ø Agonist at GABA-B receptors
Ø GABA-B receptors often expressed on presynaptic terminals of glutamatergic axons
Ø Baclofen-mediated activation of GABA-B receptors causes inhibition of these glutamatergic axons due to
è Activation of Potassium
è Inhibition of Calcium channels
è Less glutamate released è inhibition
q Can also directly inhibit voltage-gated ion channels independently of GABA-B receptors
CLINICAL INDICATION
Ø Muscle spasm
q multiple sclerosis or traumatic partial section of spinal cord
q Pain of muscle spasm in palliative care
GABA transporter inhibition GABA transaminase inhibition
TIAGABINE VIGABATRIN
à The GABA membrane transporter à The enzyme GABA Transaminase (GABA-
(GAT1) moves GABA from the synapse T) degrades GABA not packed into synaptic
back into the synaptic terminal vesicles
Ø Decreasing GABAergic synaptic Ø Decreasing availability GABA for
transmission and therefore synaptic transmission and therefore
neuronal inhibition neuronal inhibition
à Tiagabine blocks the functioning of à VIGABATRIN blocks the functioning of
this transporter, thereby increasing the this enzyme, thereby increasing the amount
amount of GABA in the synapse of GABA in the synapse
Ø Increased GABAergic synaptic Ø Increased GABAergic synaptic
transmission and therefore transmission and therefore neuronal
neuronal inhibition inhibition
CLINICAL INDICATION CLINICAL INDICATION
Adjunctive treatment for epilepsy Ø Adjunctive treatment for epilepsy