Anxiolytics, sedatives and hypnotics Flashcards
What is the single most important inhibitory transmitter in the brain?
GABA
What is the single most important excitatory neurotransmitter in the brain?
Glutamate
What are the processes involved in GABA neurotransmission?
Action potential arrives down GABAergic axon.
Increase in activity in hippocampus activates GABA neurons, localised control, dampens hippocampal activity.
GABA synthesised from glutamate.
Acted on by glutamate decarboxylase (GAD)- take away one carboxyl group from glutamate to generate GABA in presynaptic nerve terminal.
GABA loaded into vesicles, vesicular pumps suck up GABA and concentrate into presynaptic vesicles.
With arrival of action potential, there is depolarisation of presynaptic terminal and exocytotic release of GABA into cleft.
GABA diffuses across cleft and interacts with postsynaptic receptors- GABA-A receptors: chloride ionophores, ion channel linked (type 1 receptors).
When GABA stimulates GABA-A receptor, protein changes conformation and momentarily open chloride ion channels- chloride influx hyperpolarises postsynaptic cell.
More difficult to excite postsynaptic cell- harder to depolarise to reach threshold membrane potential and thus action potential.
How is GABA inactivated?
Reuptake is the first step- into surrounding glial cells or back into presynaptic terminal, reduces synaptic concentration of GABA so it can be metabolised.
First enzyme of GABA metabolism is GABA-T.
What are GABA-B receptors?
G-protein coupled type 2 receptors on presynaptic terminals.
Can be stimulated to downregulate release of GABA if high synaptic concentration (negative feedback).
What is the first enzyme of GABA metabolism?
GABA transaminase (GABA-T).
What are GABA-A receptors?
Chloride ionophores, ion channel linked (type 1 receptors).
When GABA stimulates GABA-A receptor, protein changes conformation and momentarily open chloride ion channels- chloride influx hyperpolarises postsynaptic cell.
More difficult to excite postsynaptic cell- harder to depolarise to reach threshold membrane potential and thus action potential.
How is GABA synthesised from glutamate?
Acted on by glutamate decarboxylase (GAD)- take away one carboxyl group from glutamate to generate GABA in presynaptic nerve terminal.
What is the precursor to GABA?
Glutamate.
How is GABA metabolised?
GABA transaminase (GABA-T) is the first enzyme of GABA metabolism, breaks it down into succinic semialdehyde which is then broken down into succinic acid by succinic semialdehyde dehydrogenase (SSDH). Mitochondrial enzymes. Succinic acid goes back into TCA cycle. Glutamate arises from TCA cycle- GABA shunt.
What does inhibition of GABA metabolism result in?
Large increase in brain GABA.
What is sodium valproate (epilim)?
Anticonvulsant, GABA-T and SSDH inhibitor, sodium channel blocker.
What is vigabatrin (sabril)?
Anticonvulsant, GABA-T covalent inhibitor- increase in GABA in presynaptic nerve terminal, dampens hyperactivity in the brain.
What are the 4 main protein components of the GABA-A receptor complex?
GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein
What happens when GABA activates the GABA-A receptor complex?
When GABA activates receptor, binds to GABA receptor protein and causes linkage of GABA receptor protein with benzodiazepine receptor protein mediated by GABA modulin polypeptide.
Results in momentary opening of chloride channel protein, allowing chloride influx and subsequent hyperpolarisation.
What is flumazenil?
Flumazenil is a benzodiazepine antagonist- competitive.
How do benzodiazepines interact with the GABA-A receptor complex?
Benzodiazepine binds to BDZ receptor protein and facilitates the action of GABA on the chloride ion channel.
In the presence of a benzodiazepine, binding of GABA is enhanced (increased affinity), reciprocated- in the presence of GABA, binding of benzodiazepine (affinity) is increased.
How do barbiturates interact with the GABA-A receptor complex?
Barbiturate binds to barbiturate receptor protein- enhances action of GABA on chloride channel, enhance GABA binding at GABA receptor protein (increased affinity of GABA binding)- not reciprocated; at higher than therapeutic doses can cause direct agonist action on chloride channel.
What makes the action of benzodiazepines and barbiturates allosteric?
No activity alone- GABA has to be present, because they work by enhancing it.
How are benzodiazepines and barbiturates different?
Different binding sites and different mechanisms.
Benzodiazepines increase frequency of openings.
Barbiturates increase duration of openings.
Barbiturates are less selective than benzodiazepines- decrease excitatory transmission and have other membrane effects, e.g. direct opening effect on chloride channel at higher than therapeutic doses; may explain induction of surgical anaesthesia and low margin of safety.
What are the clinical uses of benzodiazepines and barbiturates?
Anaesthetics (barbiturates only: thiopentone, used as inducing agent for general anaesthetic)
Anticonvulsants (diazepam, clonazepam, phenobarbital)
Anti-spastics (diazepam)
Anxiolytics
Sedatives/hypnotics
Define anxiolytic.
Remove anxiety without impairing mental or physical activity (‘minor tranquilisers’).
Define sedative.
Reduce mental and physical activity without producing loss of consciousness.
Define hypnotic.
Induce sleep.
