Anxiolytics, Sedatives and Hypnotics Flashcards
GABA is the bodies main …
Inhibitory NT
GABA neurons as a rule are … (axon length and type of neurone)
short-axoned interneurons
What is GABA synthesised from
Glutamate
What enzyme acts on glutamate to form GABA
glutamate decarboxylase enzyme, GAD
What is needed for GABA synthesis
Glutamate, GAD, vitB6
What is needed for proper functioning of GAD
Vit B6
What type of receptor are GABA receptors
Chloride ionophores, type 1
What does GABA receptor stimulation cause
Chloride influx and hyperpolarisation
What is GABA metabolised into
SSA - succinic semialdehyde
What metabolises GABA
GABA-T
What is GABA reuptaken by
Glial cells and presynaptic terminal
What downregulates GABA release
GABAb autoreceptors on presynaptic terminals, downregulate GABA release by negative feedback
What type of receptors are GABAb autoreceptors
Type 2 G protein coupled
What metabolises SSA succinic semialdehyde
SUCCINIC SEMIALDEHYDE DEHYDROGENASE (SSDH)
What is the product of SSA succinic semialdehyde metabolism
Succinic acid
Succinic acid is the metabolic product of what?
succinic semialdehyde metabolism by SSADH
Succinic semialdelhyde is the metabolic product of what?
GABA by GABA T
Where are GABAT and SSADH enzymes found
Mitochondria
What is the use of succinic acid
Used in TCA cycle
Sodium valproate actions?
GABAT and SSADH inhibitor
Sodium valproate is an example of what type of drug?
Anticonvulsant
Vigabatrin actions?
Covalent GABAT inhibitor
Vigabatrin is an example of what type of drug?
Anticonvulsant
4 components of the GABAa receptor complex?
- GABA receptor protein
- Benzodiazepine receptor protein
- Barbiturate receptor protein
- Chloride channel protein
What modulates linkage of the GRP with the benzodiazepine RP
GABA modulin
What happens when GABA binds to the GABARP (3)
linkage of the GRP with the benzodiazepine RP, mediated by GABA modulin
- This opens the chloride channel protein, allowing chloride ions to enter the cell and cause hyperpolarization
- Also enhances the binding of BDZ to BDZRP
What happens when a benzodiazepine binds to the BDZRP (1)
- This enhances the action of GABA on the chloride ion channel and enhances the affinity of GABA binding to GRP
What happens if we bind a barbiturate to a BRP (normal and high doses) (2+1)
- We get enhancement of GABA action of the chloride channel
- We also get enhanced affinity of GABA binding to the GABARP
- At high doses, we can get a direct effect of the drug on the chloride channel
What is bicuculline
competitive GABAA receptor antagonist
What is - FLUMAZENIL
competitive benzodiazepine antagonist
Example of a competitive benzodiazepine antagonist
FLUMAZENIL
Example of a competitive GABAA receptor antagonist
bicuculline
Explain the allosteric effects of BDZ and barbiturates, what dose is this
Therapeutic doses, neither drug have any activity. They enhance GABAs action
BARB/BDZ - which has Cl channel activity at a high dose?
BARB
How do BDZ potentiate GABA exactly
Increase frequency of the opening of the Cl channels
How do BARBs potentiate GABA exactly
Increase duration of the opening of the Cl channels
What drug family Increases duration of the opening of the Cl channels
BARB
What drug family Increases frequency of the opening of the Cl channels
BDZ
Which is more selective, BDZ or BARB, what does this mean X drug can also be used for
BDZ, so BARBs can also be used for surgical anaesthesia
Margin of safety of BARBs? Why
Low selectivity leading to low margin of error
Clinical uses of BARBs? (4)
Anaesthetics
Anxiolytics
Sedatives/hypnotics
Clinical uses of BDZ (3)
Anti-spastics
Anxiolytics
Sedatives/hypnotics
Definition of anxiolytic?
REMOVE ANXIETY WITHOUT IMPAIRING MENTAL OR PHYSICAL ACTIVITY (‘MINOR TRANQUILLISERS’)
Definition of sedative?
REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS
Definition of hypnotic?
INDUCE SLEEp
Ideal criteria for anxiolytics/sedatives/hypnotics? (6)
- Have a wide margin of safety
- Not depress respiration
- Produce natural sleep (hypnotics)
- Not interact with other drugs
- Not produce ‘hangovers’
- Not produce dependence
Example of a barbiturate?
Amobarbital
Amobarbital is an example of?
BARB
Unwanted effects of BARBs? (6)
- Low safety margins Depress respiration, O.D.s can be lethal
- Alter natural sleep (decrease REM) Hangovers/irritability
- Enzyme inducers (if co-administered with other drugs that are metabolized with same drug, they’ll effect the metabolism of the other drug)
- Potentiate effect of other CNS depressants (e.g. alcohol)
- Tolerance
- Dependence Withdrawal syndrome (insomnia, anxiety, tremor, convulsions, death)§
Admin of BDZ?
Oral/IV
Lipid solubility of BDZ?
HIgh
Plasma protein binding of BDZ?
High
What metabolises BDZ?
Liver microsomal enzymes
How are BDZ excreted?
In urine as glucoronide conjugates
Duration of action of BDZ?
Varied
how is a longer duration of action achieved by BDZ?
Active metabolites or a slower metabolism of it
T1/2 life of diazepam
32 hours
T1/2 life of temazepam
8h
T1/2 life of oxazepam
8h
Examples of a common anxiolytic Benzo?
diazepam (valium)
What are long lasting benzos used for
anxiolytics
What are short lasting benzos used for
sedatives/hypnotics
Advantages of using BDZ? (3)
- Wide margin of safety:
O.D. leads to prolonged sleep (this sleep is rousable)
O.D. can be treated with I.V. FLUMAZENIL (competitive antagonist) - Only have a mild effect on REM sleep
- Do not induce liver enzymes
Side effects of benzos? (5)
- Sedation, confusion, amnesia, ataxia (impaired manual skills)
- Potentiate other CNS depressants (e.g. alcohol, BARBs)
- Tolerance (less than BARBs – BZs only show ‘tissue’ tolerance)
- Dependence:
Withdrawal syndrome similar to BARBs but less intense
Withdraw them slowly - Free plasma concentration of BZs is increased by aspirin, heparin etc.
Other than BARB and BDZ, what can you use as a sedative/hypnotic
Zopiclone
Use of zopiclone
sedative/hypnotic
Other than BARB and BDZ, what other classes of drugs can you use as anxiolytics
Antidepressants Antiepileptics Antipsychotics Propranolol beta blocker Buspirone
