Anxiolytics Flashcards
GABA is the most important ….. NT in the brain
- GABA is the most important inhibitory NT in the brain
What is GABA synthesised from and what enzmye carries out this reaction, also what must be present for the enzyme to function properly?
- Glutamate (+GAD enzyme) → GABA
- GAD enzyme requires the presence of vitamin B6 to function properly
1) What are the 2 GABA receptors, where are they located, and what type of receptors are they?
2) What is the function of the one not involved in the inhibitory action of GABA?
1)
- GABA-A - on post-synaptic membranes - type 1 ion-channel-linked chloride ionophores
- GABA-B - on pre-synaptic membranes - type 2 (G-protein coupled)
2)
- GABA-B receptors are regulatory receptors located on the pre-synaptic membranes - they regulate GABA transmission
Outline how GABA has its inhibitory effect, mentioning detail on the GABA receptor involved
GABA acts on GABA-A receptors on post-synaptic membranes to induce chloride influx - hyperpolarises the neurone - therefore has an inhibitory effect
Outline the metabolism of GABA, and then circle round to GABA formation (describe how it is linked to the TCA cycle)
- GABA reuptake either into glial cells surrounding the synapse or back into the pre-synaptic neurone occurs - thereby reducing the synaptic concentration of GABA and allowing its metabolism
- GABA (+GABA-Transaminase) → Succinic semi-aldehyde
- Succinic semi-aldehyde (+Succinic semi-aldehyde dehydrogenase) → Succinic Acid
- Succinic acid goes back into the TCA cycle
- In the TCA cycle you eventually form glutamate
- This glutamate is then used for conversion into GABA using GAD in the presence of vitamin B6
Name 2 anxiolytic drugs that target GABA metabolism and outline their modes of action
- Sodium valproate
* GABA-Transaminase and Succinic Semi-Aldehyde Dehydrogenase inhibitors, thereby preventing both stages of GABA metabolism, so preserves and potentiates the inhibitory efffects of GABA - Vigabatrin
* GABA-Transaminase inhibitor, thereby preventing the first stage of GABA metabolism, so preserves and potentiates the inhibitory effects of GABA
What are the 4 main proteins that GABA-A receptors are composed of?
- GABA receptor protein
- Benzodiazepine receptor protein
- Barbiturate receptor protein
- Chloride channel protein
Describe in detail how GABA has its inhibitory effect, knowing the complexes within the GABA-A receptor
- GABA binds the GABA receptor protein complex on the GABA-A receptor on the post-synaptic membranes of target neurones
- When this happens, GABA receptor protein complex links with the benzodiazepine receptor complex - this is mediated by GABA modulin
- This linkage causes temporary opening of the cloride channel within the GABA-A receptor
- There is therefore Cl- inclux which causes hyperpolarisation which makes it harder for depolarisation to occur for an action potential - hence the inhibitory effects of GABA
Name a GABA-A receptor antagonist and expand further on its mode of action
- Bicuculline
- Competes with GABA for its binding site on the GABA receptor protein complex on the GABA-A receptor
Describe in detail how benzodiazepines have their effect to potentiate GABA, knowing the complexes within the GABA-A receptor
- Benzodiazepines bind the benzodiazepine receptor protein complex on the GABA-A receptor. It then has its effects:
- Binding of benzodiazepines to its receptor on GABA-A facilitates binding of GABA to the GABA receptor protein complex on the GABA-A receptor. This is a reciprocal effect (i.e. subsequent GABA binding also facilitates benzodiazepine binding to their receptor complexes on the GABA-A receptor)
- Directly facilitates GABA’s ability to open the calcium ion channels in the GABA-A receptors - it increases the frequency of chloride channel opening
What is Flumezanil - what does it do?
- Competitive benzodiazepine antagonist - competes with benzodiazepines for the benzodiazepine receptor protein on the GABA-A receptor
1) Describe in detail how barbiturates have their effect to potentiate GABA, knowing the complexes within the GABA-A receptor
2) Describe how barbiturates can have a depressant effect in isolation, which is not via GABA transmission, and when does this occur?
3) Apart from promoting inhibition, how else can barbiturates have an inhibitory / depressant effect?
1)
- Barbiturates bind the barbiturate receptor protein complex on the GABA-A receptor. It then has its effects including:
- Facilitating GABA’s ability to open chloride channels within the GABA-A receptor - increases the duration of chloride channel opening
- Facilitates the binding of GABA to the GABA receptor protein complex on the GABA-A receptor
2)
- At high barbiturate concentration, the barbiturates can have direct effects on opening of calcium channels
3)
- Barbiturates can have a direct antagonistic effect against the action of glutamate (an excitatory NT) - so inhibits the excitatory signals
1) Why do barbiturates and benzodiazepines only have an effect in the presence of GABA neurotransmission - why wouldn’t it work in isolation?
2) What is an exception to this rule - when would you get isolated effect?
1)
- Because they work by allosteric binding in order to potente GABA transmission in order to indirectly have an inhibitory / depressant effect - they do not have direct inhibitory effects
2)
- At high concentrations, barbiturates have a direct effect to open the chloride channels on the GABA-A receptors
1) Which are less selective - barbiturates or benzodiazepines?
2) How does the reduced selectivity make it useful - give a use
3) Which are more dangerous - barbiturates or benzodiazepines and why?
1)
- Barbiturates are less selective than benzodiazepines
2)
- It has other uses - for example as a surgical anaesthetic
3)
- Barbiturates due to its lower selectivity and also because it causes respiratory depression upon overdose unlike benzodiazepines
- Also benzodiazepines can be antagonised using flumezanil in the event of OD, unlike barbiturates
Give 5 clinical uses of barbiturates / benzodiazepines - one of them is ONLY a BARBITURATE use
- Anaesthetics - only barbiturates
- Anti-convulsants
- Anti-spastics
- Anxiolytics
- Sedatives / hypnotics
Define what anxiolytics do, and what is another name for them?
- Remove anxiety without impairing physical or mental health
- ‘Minor tranquilisers’
Define what sedatives do
- Reduce mental and physical activity without causing loss of consciousness
Define what hypnotics do
- Induce sleep
Name a powerful barbiturate sedative / hypnotic
- Amobarbital - used for severe insomnia
Give 3 basic structural features of the chemical structure of barbiturates
- 6 ring structure
- 4 C’s in a ring
- 2 N’s
What are the unwanted effects of barbiturates?
- Low safety margins as they depress respiration → lethal
- Alter natural sleep (decrease REM sleep) → hangovers and irritability
- Enzyme inducers - barbiturates induce microsomal enzymes - so avoid co-administration
- Potentiate other CNS depressants (e.g. alcohol)
- Tolerance
- Dependence: withdrawal symtoms, insomnia, anxiety, tremor, convulsion, death
Give a characteristic chemical structural feature of benzodiazepines
- Tricyclic - i.e. three ring structure
Give 3 key benzodiazepines
DOT
- Diazepam
- Oxazepam
- Temazepam
What does Flumezanil do, and how does the structure of Flumezanil allow it to have its effect?
- Flumezanil is a competitive benzodiazepine receptor antagonist
- It has the same tricyclic (3-ring) structure as benzodiazepines which enables it to compete for the benzodaizepine receptors
What is the main use of benzodiazepines - excluding sedative / hypnotic?
- Anti-convulsant - epilepsy - status epilepticus
Describe the distribution of benzodiazepines in terms of its pharmacokinetics
- Bind plasma proteins strongly
- Highly lipid soluble
Describe the main route of phase 2 metabolism of benzodiazepines
- Mainly glucuronide conjugates
Describe the excretion of benzodiazepines
- Excreted in the urine as glucuronide conjugates
Describe the duration of action of benzodiazepines
- Short-acting vs long-acting
How are long-acting benzodiazapines, long-acting?
- Slow metabolism
- Generate active metabolites
1) Name 2 short-acting benzodiazepines
2) Name 1 long-acting benzodiazepines
1)
- Oxazepam
- Temazepam
2)
- Diazepam
Describe how oxazepam is metabolised
- Oxazepam is metabolised in the liver into its glucuronide conjugate
Describe how temazepam is metabolised
- Temazepam is metabolised into oxazepam
- Oxazepam is then metabolised into its glucuronide conjugates
Describe how diazepam is metabolised and thus explain why it is a long-acting benzodiazepine
There are 2 routes:
EITHER:
- Diazepam is metabolised into Temazepam
- Temazepan is then metabolised into Oxazepam
- Oxazepam is then metabolised into its inactive glucuronide conjugate
OR:
- Diazepam is metabolised into nordiazepam - an active metabolite
- Nordiazepam also is reversibly converted into chlordiazepoxide which is another active metabolite
- Ultimately nordiazepam is then metabolised into oxazepam which is then metabolised into its inactive glucuronide conjugate
THEREFORE IT IS CONSIDERED A LONG-TERM METABOLITE BECAUSE…
of the active metabolites that it generates because then you take longer to metabolise both the diazepam AND the active metabolites it is metabolised into
Name three benzodiazepines used particularly for their anxiolytic effects
- Diazepam
- Chlordiazepoxide
- Nitrazepam
Apart from for its short-acting metabolic effects, when else could it be preferential to use short-acting benzodiazepines rather than long-acting ones?
- If a patient has hepatic impairment, this would impair the ability to metabolise the benzodiazepines, thereby prolonging their effects, so you give a short-acting benzodiazepine such as oxazepam
What are the advantages of using benzodiazepines over barbiturates?
- Wider margin of safety - in the event of overdose this does not lead to fatal consequences as readily like respiratory distress as with barbiturates
- You can also administer flumazenil in the event of overdose which is a competitive benzodiazepine antagonist to counter the overdose
- Does not alter REM sleep as much as barbiturates - so less ‘hangover’ feeling
- Do not induce liver (microsomal) enzymes like barbiturates do so less danger with co-adminstering with other drugs
Give the unwanted effects of benzodiazepines (5)
- Confusion / ataxia
- Potentiate other CNS depressants like alcohol
- Tolerance - only tissue tolerance not pharmacokinetic tolerance
- Dependence
- Free plasma concentration of benzodiazepines increases when you co-administer aspirin and heparin because these are also plasma protein bound and so compete with them for the plasma proteins
1) Name a drug that is a sedative / hypnotic but is neither a benzodiazepine nor a barbiturate and describe its mode of action
2) What class of drugs does it belong to?
3) Give an advantage of this drug
1)
- Zopiclone
- Benzodiazepine receptor agonist (but it is NOT a benzodiazepine)
2)
- Cyclopyrrolone
3)
- Minimal hangover effects - as it does not alter REM sleep much
Name some drug types and some named examples or directly name some drugs that can also be used as anxiolytics that are neither benzodiazepines nor barbiturates
- Anti-depressants
- SSRIs
- Anti-epileptics
- Valproate
- Tiabigine
- Anti-psychotic drugs
- Olanzapine
- Quetiapine
- Propranolol
- Non-selective beta-blocker - improves the physical symptoms of anxiety
- Buspirone
- 5-HT1A agonists
