5.3 GABAergic Transmission & Anxiolytics, Sedative Hypnotics Flashcards
Where is GABA distributed in?
cerebral cortex, cerebellum, hippocampus, corpus striatum, hypothalamus, dorsal horn of spinal cord (influences information from primary afferent fibres entering the cord) and the peripheral nervous system (minor):
• Most neurones (at 30% of synapses) in the brain respond to GABA → those utilising GABA as a neurotransmitter are short inhibitory interneurones (short axons)
o Function: _____________
• GABA is also involved in the longer GABAergic tracts (e.g. striato-nigral tract – descending tract from ______________- , cerebellar tract – incoming afferent cerebellar tracts)
• Possesses widespread inhibitory actions in the CNS at pre- and post-synaptic sites
regulate brain activity;
corpus striatum to substantia nigra
The original precursor (______________-) for GABA biosynthesis comes from the Krebs cycle in the GABAergic neurones:
• Converted to glutamate via ________________, then to GABA via __________________ → specific for inhibitory GABAergic neurones
• After GABA performs its function, it is metabolised by GABA-T into ________________, which is converted into succinate by succinic semialdehyde dehydrogenase (SSDH) → returns to the Krebs cycle
• GABA shunt accounts for 10% of the activity of the Krebs cycle in GABAergic neurones
α-oxoglutarate;
GABA transaminase (GABA-T);
glutamate decarboxylase (GAD);
succinic semialdehyde
GABA is stored in presynaptic vesicles after synthesis, which have _____________ to take up more GABA into the vesicles (high concentration of GABA accumulates):
• Arrival of action potentials down the short axons of the inhibitory interneurone causes membrane depolarisation and opening of voltage-sensitive Ca2+ channels
• Influx of Ca2+ causes exocytosis of GABA into the synaptic cleft and binding to postsynaptic GABAergic receptors
surface transporters
GABA is inactivated by reuptake into ________________ via protein carrier molecules (saturable):
• Na+-dependent process requiring energy as it generates a concentration gradient within the cells
• Metabolised after uptake into the neurones or glial cells → acted on by __________________ (mitochondrial enzymes)
• Inhibition of GABA-T or SSDH causes a large increase in the concentration of GABA in the brain → enhances GABA-mediated inhibition
• ___________________ act partially via inhibition of GABA metabolism to slow down its breakdown → used as anticonvulsants/antiepileptics
GABAergic neurones and surrounding glial cells;
neurones or glial cells;
GABA-T and SSDH;
Sodium valproate (Epilim) or vigabatrin (Sabril)
What is the type, structure and mechanism of a GABA A receptor?
- Type 1 (ionotropic)
- Pentameric (commonly 2α1β2γ2)
- Linked to Cl- channel → conformational change leads to opening of the channels → Cl- influx (hyperpolarisation; IPSP) → inhibition of firing
What is the type, structure and mechanism of a GABA B receptor?
- Type 2 (G-protein coupled)
- 7 transmembrane domains (coupled to Gi and adenylyl cyclase)
- Gi negatively linked to adenylate cyclase → reduced cAMP levels → reduced Ca2+ conductance → reduced neurotransmitter release
What is the definition of autoreceptors?
inhibit GABAergic neurone release of GABA (negative feedback)
What is the definition of heteroreceptors?
localised on nerve terminals which use other neurotransmitters (e.g. increase dopaminergic neurone release of dopamine) → regulates concentration of other neurotransmitters
What are some specific GABA A agonists?
- GABA (non-selective)
- Muscimol (selective)
- Benzodiazepines, barbiturates (clinically useful)
What are some specific GABA B agonists?
- GABA (non-selective)
- Baclofen (selective; therapeutically used as a muscle relaxant and anti-spastic drug):
–> Muscle relaxant: acts in the spinal cord to reduce the outflow of action potential to skeletal muscle fibres
–> Anti-spastic drug: treat spasticity
following e.g. multiple sclerosis/spinal
cord damage
The GABAA receptor has a pentameric organisation (consists of 5 main proteins) which allows Cl- ions to pass through the centre (contains Cl- channel) into the postsynaptic cell. What are the 5 proteins?
GABA receptor protein, benzodiazepine receptor protein, barbiturate receptor protein, Cl- channel protein and GABA modulin protein (links GABA receptor protein to benzodiazepine receptor protein)
What are the effects of activating the GABA receptor protein?
Triggers linkage between GABA receptor protein and benzodiazepine receptor protein by GABA modulin:
• Allows opening of the Cl- channel protein → Cl- influx → hyperpolarisation → inhibition
What are the effects of activating the Benzodiapene receptor protein?
- Facilitates underlying action of GABA (increases Cl- conductance)
- Enhances binding of GABA to GABA receptor site (reciprocal arrangement – binding of benzodiazepine to benzodiazepine receptor protein is also enhanced in presence of GABA)
What are the effects of activating the Barbituate receptor protein?
- Facilitates action of GABA (enhances Cl- influx caused by GABA binding to GABA receptor)
- Enhances binding of GABA to GABA receptor (not reciprocal)
- Increases Cl- influx into postsynaptic cell (direct action on Cl- channel)
Bisculline is a GABA A antagonist. How does it inhibit?
Competitive GABAA receptor antagonist (binds to GABAA receptor → competes with GABA for binding)
Picrotoxin is a GABA A antagonist. How does it inhibit?
non-competitive; binds to Cl- channel and inhibits flow into postsynaptic neurone
Flumazenil is a GABA A antagonist. How does it inhibit?
Competitive benzodiazepine antagonist (competes with benzodiazepines for the binding site)
How is BDZ distributed?
binds plasma proteins strongly, highly lipid-soluble (wide distribution)
How is BDZ administered?
oral (well absorbed; peak plasma conc. achieved in about 1h), IV (e.g. for status epilepticus)
How is BDZ metabolised?
usually extensive (in liver)
How is BDZ excreted?
in urine via the kidneys (as glucuronide conjugates)
Benzodiazepines have many advantages (makes them more clinically useful):
1. Wider margin of safety (overdose results in prolonged sleep → patient still rousable) compared to death in overdose of BARBs
• ____________: IV antidote to overdose (competitive BDZ antagonist)
2. Only mild effect on ____________
3. Does not induce ________________
Flumazenil;
REM sleep;
liver enzymes (less drug interactions)
What are the ideal characteristics of the drugs?
- Wide margin of safety
- Not depress respiration
- Produce natural sleep (hypnotics)
- No drug interactions
- Not produce hangovers
- Not produce dependence
What BDZ so you use in an axiolytic?
Long acting BDZs
- Diazepam (Valium)
- Chlordiazepoxide (Librium)
- Nitrazepam
What BDZ should you use in patients with hepatic impairment + as an antiolytics?
short-acting BDZs (e.g. oxazepam – t1/2 8 hours) may be more useful → metabolised more slowly)
What BDZs do you use as a sedative/ hypnotic
- Temazepam
- Oxazepam
- Nitrazepam (t1/2 28 hours) used for hypnotic activity (for patients who also require a daytime anxiolytic effect)
- Zopiclone (t1/2 5 hours) → BDZ-like drug (not BDZ) → actions on BDZ receptors and useful hypnotic activity
Which barbituate is used as an anaesthetic?
thiopentone – very lipid soluble; used in induction of GA
What barbituate can you use as a hypnotic in patients not responding to BDZ and has severe, intractable insomnia?
Amobarbital (t1/2 20 – 25 hours)
what would you use as a sedative for children and the elderly?
Chloral hydrate (pro-drug) → converted to the active trichloroethanol in the liver (mechanism unknown; but wide margin of safety for children and the elderly)
Other anxiolytic:
1) Buspirone (__________________ agonist; slow onset of action → maximal effects may take days/weeks, few side effects)
2) ___________ (non-selective β receptor antagonist → improves physical symptoms of anxiety like β1-mediated tachycardia and β2-mediated tremor)
3) ____________ (mechanism unknown; therapeutically useful anxiolytic activity and relatively mild side effects (e.g. sedation, ataxia) → usually used as a backup for BDZs
5HT1A/serotonin;
Propranolol;
Pregabalin
What are the side effects of BDZ?
- Sedation (when used as an ___________) and confusion
- Ataxia (impaired manual skills)
- Potentiates other CNS depressants (alcohol, opioids, BARBs)
- __________ (less marked than BARBs)
- Dependence (withdrawal syndrome similar to BARBs but less intense) → withdraw slowly (over days to weeks)
- Free [plasma] of BDZ increases when co-administered with other drugs that bind to plasma proteins (e.g.______________) → BDZs displaced from plasma proteins
anxiolytic;
Tolerance ;
aspirin, heparin
What are the side effects of barbituates?
- Low safety margin (depress _____________) → overdose is lethal
- Alters natural sleep (reduced ___________) → hangovers/irritability
- Enzyme inducers (long-term use → increased activity of liver microsomal enzymes → drug interactions with those metabolised by same system)
- Potentiates other CNS depressants (alcohol, opioids)
- Tolerance (may develop with repeated administration)
- Dependence: withdrawal syndrome (insomnia, anxiety, tremor, convulsions, death)
respiration;
REM
