GABA Drugs
GABA is made from glutamate using an enzyme that is only found in GABA neurones.
It binds GABA(A) receptors which are ionotropic and permeable to Cl- ions which hyperpolarizes neurones
It also binds to GABA(B) receptors, which are metabotropic and Gi linked, which inhibits neurones.
General anaesthetics and alcohol are positive modulators of GABA receptors.
Barbiturates – Phenobarbital, thiopental
These are GABA positive modulators at low doses but can also directly increase GABA receptor activity in the absence of endogenous GABA.
This means that they have a very low therapeutic index.
Phenobarbital is used as an anticonvulsant.
Thiopental can be used as a general anaesthetic. It is rapidly acting but has largely been superseded by propofol.
Side effects
Sedation
Respiratory depression
Porphyrin synthesis
Benzodiazepines – Diazepam, midazolam (suffix = -am)
These are allosteric modulators of GABA(A) receptors which bind to the alpha subunit.
They increase the binding of GABA to its receptor, without directly activating the receptor itself, unlike barbiturates.
They have superseded barbiturate use and dose-dependently inhibit the CNS.
Short and intermediate-acting benzodiazepines (midazolam, lorazepam) are used for insomnia, seizures, and the short-term management of anxiety disorders.
Diazepam is used to treat muscle spasms.
Midazolam is used pre-operatively for sedation and to reduce anxiety in procedures such as endoscopy and cardiac catheterization.
Side effects
Tolerance and dependence
Daytime drowsiness (hangover), and confusion (a very common cause of confusion/amnesia in elderly)
Respiratory and CNS depression, especially when taken in combination with alcohol
Overdose is treated with supportive care/flumazenil
Flumazenil
This is a competitive antagonist of the benzodiazepine receptor.
It is used to treat benzodiazepine overdoses to reverse CNS side effects.
In addition, it can be used to accelerate recovery from anaesthetics.
Side effects
Increases the risk of seizures, so must be used with extreme caution when reversing benzodiazepine overdose.
Z drugs – Zopiclone, Zolpidem
These bind to the same site as the benzodiazepines.
However, they are more specifically used for their sedative effects.
They are used for the short-term treatment of insomnia due to their rapid action.
They have weaker activity elsewhere, which means they have less potential for tolerance, dependence and rebound insomnia.
GABA-b agonists – Baclofen
This acts on the spinal cord to inhibit synaptic transmission.
It is used as an antispasmodic to reduce hyperexcitability in stroke, multiple sclerosis and other upper motor neurone lesions.
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