Anxiolytics, Sedatives and Hypnotics Flashcards
Describe the GABA-ergic synapase
See slide
Most important inhibitory transmitter in the brain. Short axon interneurones release GABA - have an regular inhibitory role in the brain. They are regional inhibitory control interneurones.
GABA is synthesised from glutamate. Glutamate is an excitatory transmitter. GAD (glutamate decarboxylase) enzyme converts glutamate to GABA. Stored in presynaptic vesicles.
GABA stimulates post synaptic receptors (postsynaptic Cl- ionophore receptor (GABA A - type 1 receptor)). This causes a hyperpolarisation of the post-synaptic cell = it makes it harder to depolarise = less excitable = inhibitory response.
GABA is reuptaken back into the presynaptic terminal and the glial cells. GABA is metabolised after reuptake. GABA-T (transaminase) breaks GABA down into SSA (succinate semialdehyde).
GABA A - inhibitory of postsynaptic receptors; reduce the synthesis and release of GABA
GABA B - Auto-receptors regulating GABA release; presynaptic receptor
Describe the process of GABA metabolism?
GABA –> succinic semialdehyde (SSA)
Catalysed by GABA transaminase
Succinic semialdehyde –> succinic acid (used in the TCA cycle - interestingly the TCA will then generate more GABA)
Catalysed by succinic semialdehyde dehydrogenase
GABA –> SSA –> succinic acid
- GABA metabolism is performed by mitochondrial enzymes (GABA-T and SSDH)
- Inhibitors of GABA metabolism –> Increase in brain GABA
These drugs inhibit GABA metabolism: Anticonvulsant - work by raising GABA concentrations to inhibit CNS over activity.
SODIUM VALPROATE (EPILIM) - GABA-T and SSDH inhibitor
VIGABATRIN (SABRIL) - GABA-T inhibitor
Describe the GABA A receptor complex and describe BARB and BZ.
See slide - flow the numbering of the slide.
4 main proteins: GABA receptor protein, BDZ receptor protein, BARB receptor protein, GABA modulin.
- Binding of GABA opens the chloride channel.
- BDZ bind to BDZ receptor protein enhances the the affinity of GABA to the GABA protein and vice versa. It also enhances the action of GABA.
- BARBs bind to BARB receptor. They enhance the action of GABA and GABA binding is increased but this is not reciprocated. BARB can also cause a direct opening of the Cl- channels at high concentrations.
Bicuculline - GABA antagonist
Flumazenil - BDZ antagonist
BZs and BARBs :
1) No activity alone (allosteric action) - they need GABA to be present
2) Different binding sites and different mechanisms
- BZs increase frequency of openings
- BARBs increase duration of opening
3) BARBs less selective than BZs
- decreased excitatory transmission (antagonist effects on glutamate receptors)
- other membrane effects
May explain:
- induction of surgical anaesthesia
- low margin of safety
What are the clinical uses of BZs and BARBs?
- Anaesthetics (BARBs only: Thiopentone)
- Anticonvulsants (Diazepam, Clonazepam, Phenobarbital)
- Anti-spastics (Diazepam - look and muscular skeletal muscle spasticity)
- Anxiolytics
- Sedatives/Hypnotics
Define anxiolytics
Remove anxiety without impairing mental or physical activity (minor tranquillisers)
Define sedatives
Reduce mental and physical activity without producing loss of consciousness
Define Hypnotics
induce sleep
What should benzodiazepines and barbituates ideally do?
- Have a wide margin of safety
- Not depress respiration
- Produce natural sleep (hypnotics)
- Not interact with other drugs
- Not produce “hangovers”
- Not produce dependence
Describe barbiturates and give an example
See slides for structure
Range of clinical uses including as mentioned previously.
Sedative/hypnotic
- Amobarbital: Treats severe intractable insomnia. t1/2 of 20-25h
They have been super-seeded by BZ due to their negative side effects.
What are the unwanted effects of barbituates
- Low safety margins: 1) Depress respiration 2) Overdosing lethal
- Alter natural sleep (decreased REM) –> Hangovers/irritability
- Enzyme inducers, interact with a bunch of drugs
- Potentiate effect of other CNS. Depressants (e.g alcohol)
- Tolerance, tissue and pharmacokinetic tolerance
- Dependence: Withdrawal syndrome.
1) insomnia
2) Anxiety
3) Tremor
4) Convulsions
5) Death
Describe benzodiazepines
See slides for structure - Diazepam, Oxazepam and Temazepam
There is about 20 available with all act at the GABA A receptors. They all have similar potencies and profiles in activity.
The pharmacokinetics largely determine use
Describe the pharmacokinetics of BZs
Administration
- Well absorbed orally
- Peak plasma is about 1 hour
- I.V for status epilepticus
Distribution
- Bind plasma proteins strongly
- Highly lipid soluble –> wide distn
Metabolism
- usually extensive (liver)
Excretion
- Urine glucuronide conjugates
Duration of action –> vary greatly
- Short acting
- Long acting; slow metabolism and/or active metabolites
Draw out a flow diagram showing the metabolism of benzodiazepines
See slide 11
Long acting - Diazpeman
Short acting - Temazepam, Oxazepam –> excreted as glucornoide
Give example of anxiolytic?
Long acting - something that will help with anxiety throughout the day
DIAZEPAM (valium) 32h
Chlordiazepoxide (librium)
Nitrazepam
N.b OXAZEPAM; has a half life of around 8 hours. Used for patients with hepatic impairment because of its shorter half compared to diazepam.
Give examples of sedatives/hypnotics?
Shorter acting drugs to assist with diseases such as insomnia
TEMAZEPAM 8h
OXAZEPAM 8h
N.b nitrazepam; has a half life of 28 hours. Has daytime anxiolytic effect in addition to anxiety (anxiolytic)
