Anxiolytics and hypnotics Flashcards
What do these drugs target to give them their anxiolytic and hypnotic properties
They enhance GABA transmission.
What are the two main classes of GABA receptor and where are they found
GABAa and GABAb
Found on the post-synaptic membrane to mediate the effects of GABA
They are ion-channel receptors (but GABAb is metabotropic-GPCR)
Which other drug classes can have anxiolytic and sedative effects
Anti-depressants
Anti-psychotics
Anti-convulsants
What type of amino acid is GABA
Neutral
Why is GABA called GABA
Gamma amino butyric acid
This is because the amino group is on the gamma carbon of GABA
Describe the distribution of GABA neurones
Cerebral cortex Cerebellum Hippocampus Corpus striatum Hypothalamus Dorsal horn of spinal cord Relatively little in the PN
Describe the morphology of GABA neurones
They are generally short inhibitory interneurons
They inhibit the activity of localised regions (e.g they may inhibits hyperexcitabilty of the hippocampus)
Where can you find longer GABA tracts
Striato-nigral (descending version of nigro-striatal- begins in corpus striatum and ends in substantia nigra- regulating activity of dopaminergic neurones in the substantia nigra - this is a GABAergic tract
Cerebellar
Substantia nigra in the midbrain- ascending pathway to corpus striatum (bilateral pathway)- utilises dopamine- degeneration in Parkinson’s
Summarise the functions of GABA neurones in terms of CNS activity
Emotional control
Motor control
Extrapyramidal activity
Endocrine function
Describe the synthesis of GABA in the pre-synaptic terminal of a GABAergic neurone
Glutamate à GABA via GAD (Glutamate Decarboxylase).
This enzyme is exclusive to GABA nerve terminals – it is a marker for GABA neurones
Alpha-oxoglutarate (product of the Krebs Cycle) gives rise to glutamate.
The GABA synthesised is then stored in synaptic vesicles.
Describe the release of GABA into the synapse
AP arrives- Ca2+ mediated exocytosis of vesicles containing GABA
- GABA can bind to:
a. GABAAR on the postsynaptic cell à hyperpolarise cell.
b. GABABR on pre-synaptic cell à -ve inhibition of release. - functions like the alpha 2 receptor to control release of NA
GABAa= post-synaptic Cl- ionophore receptor
Describe the reuptake of GABA from the synaptic cleft
Re-uptake by Glial Cells (astrocytes) and pre-synaptic cell
GAT1- pre-synaptic cell
GAT3- glial cell
a. Glial cells – GABA-Transaminase breaks down GABA into SSA (Sunninic Semialdehyde).
b. Pre-synaptic cell – GABA-T breaks down GABA into SSA.
Or they can be simply stored in synaptic vesicles for future use.
Describe the metabolism of GABA after re-uptake into the synaptic cell or glial cell
Initially by GABA-T (GABA transaminase) to succinic semialdehyde
Succinic semialdehyde is broken down by succinic semialdehyde dehydrogenase (SSDH) to succinate
Succinate then enters the Krebs’ cycle
What does GABA reuptake depend on
Sodium dependent
Energy dependent
Describe the GABA shunt
8-10% of demand of TCA- shows how important GABA is
Alpha-oxoglutarate- leaves TCA to make glutamate to synthesise GABA
GABA broken down to succinate- which re-enters TCA
GABA that leaves TCA enters again
Where are the enzymes involved in GABA synthesis and metabolism located
GAD- cytosol
GABA-T and SSDH- mitochondrial membrane
What is a consequence of inhibiting the enzymes of GABA metabolism
An increase in the amount of GABA available in the brain.
Name two drugs that interfere with GABA metabolism and can be used as anti-covalents
Sodium valproate (acts on GABA-T and SSDH (but more so on SSDH)) - also blocks VGSC (Epilim). Vigabatrin (selective GABA-T inhibitor )- covalently binds to GABA-T (Sabril)- suicide inhibitor
Describe the different subunits of the GABAa receptor
They are ionotropic receptors (type 1) They have a pentameric structure consisting of the following subunits: · 2 x alpha · 2 x beta · 1 x gamma
Summarise the mechanism of action of GABAa receptors
GABA binding causes opening of the chloride channel leading to chloride influx
This causes hyperpolarisation of the postsynaptic neurone (inhibitory post-synaptic potential)
This causes inhibition of firing
What are the four main receptor proteins that make up GABAa
GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein
Describe the normal physiological action of GABA
GABA binds to the GABA receptor protein
GABA modulin links the GABA receptor protein and the benzodiazepine receptor protein
This results in opening of the chloride ion channel
GABA can also bind to and open the chloride channel protein directly.
What are the two main effects of benzodiazepines that facilitate GABA neurotransmission
They facilitate the GABA-mediated opening of the chloride channel
They facilitate the binding of GABA to its receptor protein (increase the affinity of GABA to the GABA binding site) – this is reciprocated
What are the three main effects of barbiturates that facilitate GABA neurotransmission
They enhance the normal physiological action of GABA
They enhance GABA binding to the GABA receptor protein (NOT reciprocated)
At higher concentrations, barbiturates can have a direct action on the chloride channel
Describe the dependene of barbiturates and benzodiazepines on GABA
BDZ and Barb require GABA to some degree to function.
Name two drugs which act as competitive antagonists of :
a) GABA
b) Benzodiazepines
Competitive antagonist for GABA- Bicuculline- used mostly experimentally- competes for GABA receptor protein
Competitive antagonist for Benzodiazepines – Flumazenil- useful for reversing the toxicity of a benzodiazepine overdose
What type of drugs are benzodiazepines and barbiturates classed as and why
They are not agonists of GABA- but positive allosteric modulators
That is they bind allosterically to the GABAa receptor and need GABA to bind also to simulate opening of the Cl- channel- they cannot do this without GABA
Describe the key differences in the function of benzodiazepines and barbiturates at the GABAa receptor
Different binding sites
Benzodiazepines – increase the frequency of chloride channel opening
Barbiturates – increase the duration of chloride channel opening
Both of these mechanisms will result in greater conductance of the Cl- channel, increasing the flow of Cl- ions through the channel and thus enhancing the action of GABA.
