Anxiolytics and hypnotics Flashcards
Describe the synthesis of GABA in the pre-synaptic neurone
Glutamate (from the TCA) is converted to GABA (in the presynaptic neuron) via Glutamate Decarboxylase
State the two receptors that GABA can bind to when released into the synapse.
What does this binding lead to in each case?
GABA can bind to:
- GABA(a) receptors (Cl- ionophores) on the postsynaptic cell => hyperpolarisation
- GABA(b) receptors (auto-rectpors) on pre-synaptic cell => regulation of GABA release into the synapse (similar to alpha2 receptors)
Describe the re-uptake and breakdown of GABA
GABA can then be re-up-taken by:
Glial cells
and/or
Pre-synaptic cell
In each case, GABA-Transaminase breaks down GABA into SSA (Succinic Semialdehyde).
In the metabolism of GABA, what is the Succinic Semialdehyde (SSA) converted into? By what enzyme?
Succinic Semialdehyde (SSA) is converted to Succinic Acid by Succinic Semialdehyde dehydrogenase (SSDH)
The enzymes involved in the synthesis and metabolism of GABA:
- GAD
- GABA-T
- SSDH
Where are they found in the cell?
GAD is found in the cytosol whilst GABA-T and SSDH are found in the mitochondrial membrane.
Inhibitors of GABA metabolism leads to what?
Give examples of drugs which do this.
Inhibitors of GABA metabolism lead to more GABA and more inhibition in the brain.
e.g. Sodium Valproate, Vigabatrin
What are the four main proteins that make up the GABA-A receptor?
GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein (in the centre)
What protein links the GABA receptor protein and the benzodiazepine receptor protein?
GABA modulin
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
Name a competitive antagonist of the GABA receptor protein.
Biciculline
Name a competitive antagonist of the benzodiazepine receptor protein.
Flumazenil
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 directly activate the chloride channel
What is the key difference in the mechanism of action of barbiturates and benzodiazepines?
Benzodiazepines – increase the frequency of chloride channel opening
Barbiturates – increase the duration of chloride channel opening
What is the relative difference in selectivity between barbiturates and benzodiazepines?
Barbs are less selective then BDZs so Barbs:
- have less excitatory transmission.
- are less safe (induce surgical anaesthesia and have a small therapeutic window)
List the clinical uses of benzodiazepines and barbiturates, give
- Anaesthetics (barbiturates only = Thiopentone)
- Anticonvulsants (Diazepam, Clonazepam, Phenobarbital)
- Anti-spastics (Diazepam)
- Anxiolytics
- Sedatives/hypnotics
Define anxiolytic.
Remove anxiety without impairing mental or physical activity
Define sedative.
Reduce mental and physical activity without producing loss of consciousness
Define hypnotic.
Induces sleep
Describe the general chemical structure of barbiturates
- Six-membered ring structure (4 carbons and 2 nitrogens)
- 2 R groups;
R1 = ethyl
R2 = phenyl/1-methylbutyl.
Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly as a sedative/hypnotic? State an unwanted effect of using this drug?
Amobarbital
Causes severe intractable insomnia.
What is the half-life of amobarbital?
20-25 hours
Barbiturates have many unwanted effects so are not a 1st line;
List some of their unwanted effects.
Small therapeutic window => depress respiration.
Reduce REM sleep (=> “hangovers”/irritability)
Enzyme inducers
Potentiate effects of other CNS depressants (e.g. alcohol)
Tolerance and dependence
Describe the chemical structure of benzodiazepines
Usually a triple-ring structure.
What do all BZDs act on? What determines which BZD is used clinically?
All act on GABA-A receptors, have similar potencies but it’s the pharmacokinetics that differentiate use
Describe the administration of benzodiazepines.
Well absorbed per orally
Peak plasma concentration after about 1 hour
When would you give IV benzodiazepines?
Treatment of status epilepticus
Describe the distribution of benzodiazepines.
Highly lipid soluble
Bind strongly to plasma proteins
Describe the metabolism of benzodiazepines.
Extensively metabolised in the liver
Describe the excretion of benzodiazepines.
Excreted in the urine as glucuronide conjugates
Describe the duration of action of benzodiazepines.
Varies a lot
This allows classification as short-acting and long-acting benzodiazepines
What makes long-acting benzodiazepines have a long duration of action?
They have slower metabolism
and/or
They generate active metabolites
Name two short-acting benzodiazepines.
Oxazepam
Temazepam
Name a long-acting benzodiazepine.
Diazepam
Describe the metabolism of oxazepam.
It is metabolised straight to its glucuronide conjugate (t1/2 = 8 hours)
Describe the metabolism of temazepam.
Metabolised to oxazepam and then to the glucuronide conjugate
Describe the metabolism of diazepam.
Metabolised via temazepam and oxazepam to the glucuronide conjugate
Some diazepam is metabolised to nordiazepam and then oxazepam
Name three drugs that are used as anxiolytics.
General rule – long-acting benzodiazepines
Diazepam
Chlordiazepoxide
Nitrazepam
Under what condition would you use a short-acting benzodiazepine as an anxiolytic?
Hepatic impairment – this means that the benzodiazepines will be metabolised more slowly
Drug of choice = oxazepam
Name two drugs that are used as sedatives/hypnotics.
General rule – short-acting benzodiazepines
Oxazepam
Temazepam
Name a long acting drug that might be used as a sedative/hypnotic.
Nitrazepam (t1/2 = 28 hours)
What are the unwanted effects of benzodiazepines?
Sedation
Confusion
Ataxia
Potentiate other CNS depressants (e.g. alcohol)
Tolerance
Dependence
Free plasma concentration of benzodiazepines can be increased by giving aspirin and heparin
What are the advantages of benzodiazepines over barbiturates?
Wide margin of safety;
- Overdose causes prolonged sleep (but this is rousable)
- Flumezanil can be given IV if a patient has overdosed
- Mild effect on REM sleep
- Do NOT enhance liver enzymes
Name a sedative/hypnotic that isn’t a benzodiazepine. What class of drug does this fall into?
Zopiclone;
- cyclopyrrolone
- short-acting (t1/2 = 5 hours)
- acts on the benzodiazepine receptor but it is not a benzodiazepine
- has fewer hangover effects but dependency is still an issue
What drug is used to control the physical symptoms of anxiety?
Propranolol
Name a new drug that has started being used as an anxiolytic.
Buspirone – 5HT1A agonist
This has relatively few side effects and causes less sedation than benzodiazepines
Downside: slow onset of action (maximal anxiolytic effects are not seen for a number of days/weeks)
