Anxiolytics

Question 1

GABA is the most important ….. NT in the brain

Answer 1

• GABA is the most important inhibitory NT in the brain

Question 2

What is GABA synthesised from and what enzmye carries out this reaction, also what must be present for the enzyme to function properly?

Answer 2

• Glutamate (+GAD enzyme) → GABA
• GAD enzyme requires the presence of vitamin B6 to function properly

Question 3

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?

Answer 3

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

Question 4

Outline how GABA has its inhibitory effect, mentioning detail on the GABA receptor involved

Answer 4

GABA acts on GABA-A receptors on post-synaptic membranes to induce chloride influx - hyperpolarises the neurone - therefore has an inhibitory effect

Question 5

Outline the metabolism of GABA, and then circle round to GABA formation (describe how it is linked to the TCA cycle)

Answer 5

• 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

1. GABA (+GABA-Transaminase) → Succinic semi-aldehyde
2. 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

Question 6

Name 2 anxiolytic drugs that target GABA metabolism and outline their modes of action

Answer 6

1. 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
2. Vigabatrin
   * GABA-Transaminase inhibitor, thereby preventing the first stage of GABA metabolism, so preserves and potentiates the inhibitory effects of GABA

Question 7

What are the 4 main proteins that GABA-A receptors are composed of?

Answer 7

1. GABA receptor protein
2. Benzodiazepine receptor protein
3. Barbiturate receptor protein
4. Chloride channel protein

Question 8

Describe in detail how GABA has its inhibitory effect, knowing the complexes within the GABA-A receptor

Answer 8

1. GABA binds the GABA receptor protein complex on the GABA-A receptor on the post-synaptic membranes of target neurones
2. When this happens, GABA receptor protein complex links with the benzodiazepine receptor complex - this is mediated by GABA modulin
3. This linkage causes temporary opening of the cloride channel within the GABA-A receptor
4. 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

Question 9

Name a GABA-A receptor antagonist and expand further on its mode of action

Answer 9

• Bicuculline
• Competes with GABA for its binding site on the GABA receptor protein complex on the GABA-A receptor

Question 10

Describe in detail how benzodiazepines have their effect to potentiate GABA, knowing the complexes within the GABA-A receptor

Answer 10

• Benzodiazepines bind the benzodiazepine receptor protein complex on the GABA-A receptor. It then has its effects:

1. 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)
2. Directly facilitates GABA’s ability to open the calcium ion channels in the GABA-A receptors - it increases the frequency of chloride channel opening

Question 11

What is Flumezanil - what does it do?

Answer 11

• Competitive benzodiazepine antagonist - competes with benzodiazepines for the benzodiazepine receptor protein on the GABA-A receptor

Question 12

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?

Answer 12

1)

• Barbiturates bind the barbiturate receptor protein complex on the GABA-A receptor. It then has its effects including:

1. Facilitating GABA’s ability to open chloride channels within the GABA-A receptor - increases the duration of chloride channel opening
2. 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

Question 13

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?

Answer 13

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

Question 14

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?

Answer 14

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

Question 15

Give 5 clinical uses of barbiturates / benzodiazepines - one of them is ONLY a BARBITURATE use

Answer 15

1. Anaesthetics - only barbiturates
2. Anti-convulsants
3. Anti-spastics
4. Anxiolytics
5. Sedatives / hypnotics

Question 16

Define what anxiolytics do, and what is another name for them?

Answer 16

• Remove anxiety without impairing physical or mental health
• ‘Minor tranquilisers’

Question 17

Define what sedatives do

Answer 17

• Reduce mental and physical activity without causing loss of consciousness

Question 18

Define what hypnotics do

Answer 18

• Induce sleep

Question 19

Name a powerful barbiturate sedative / hypnotic

Answer 19

• Amobarbital - used for severe insomnia

Question 20

Give 3 basic structural features of the chemical structure of barbiturates

Answer 20

• 6 ring structure
• 4 C’s in a ring
• 2 N’s

Question 21

What are the unwanted effects of barbiturates?

Answer 21

• 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

Question 22

Give a characteristic chemical structural feature of benzodiazepines

Answer 22

• Tricyclic - i.e. three ring structure

Question 23

Give 3 key benzodiazepines

Answer 23

DOT

• Diazepam
• Oxazepam
• Temazepam

Question 24

What does Flumezanil do, and how does the structure of Flumezanil allow it to have its effect?

Answer 24

• 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

Question 25

What is the main use of benzodiazepines - excluding sedative / hypnotic?

Answer 25

* Anti-convulsant - epilepsy - status epilepticus

Question 26

Describe the distribution of benzodiazepines in terms of its pharmacokinetics

Answer 26

* Bind plasma proteins strongly * Highly lipid soluble

Question 27

Describe the main route of phase 2 metabolism of benzodiazepines

Answer 27

* Mainly glucuronide conjugates

Question 28

Describe the excretion of benzodiazepines

Answer 28

* Excreted in the urine as glucuronide conjugates

Question 29

Describe the duration of action of benzodiazepines

Answer 29

* Short-acting vs long-acting

Question 30

How are long-acting benzodiazapines, long-acting?

Answer 30

* Slow metabolism * Generate active metabolites

Question 31

1) Name 2 short-acting benzodiazepines 2) Name 1 long-acting benzodiazepines

Answer 31

1) 1. Oxazepam 2. Temazepam 2) * Diazepam

Question 32

Describe how oxazepam is metabolised

Answer 32

* Oxazepam is metabolised in the liver into its glucuronide conjugate

Question 33

Describe how temazepam is metabolised

Answer 33

* Temazepam is metabolised into oxazepam * Oxazepam is then metabolised into its glucuronide conjugates

Question 34

Describe how diazepam is metabolised and thus explain why it is a long-acting benzodiazepine

Answer 34

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

Question 35

Name three benzodiazepines used particularly for their anxiolytic effects

Answer 35

* Diazepam * Chlordiazepoxide * Nitrazepam

Question 36

Apart from for its short-acting metabolic effects, when else could it be preferential to use short-acting benzodiazepines rather than long-acting ones?

Answer 36

* 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

Question 37

What are the advantages of using benzodiazepines over barbiturates?

Answer 37

* 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

Question 38

Give the unwanted effects of benzodiazepines (5)

Answer 38

1. Confusion / ataxia 2. Potentiate other CNS depressants like alcohol 3. Tolerance - only tissue tolerance not pharmacokinetic tolerance 4. Dependence 5. 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

Question 39

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

Answer 39

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

Question 40

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

Answer 40

* 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-HT_1A agonists