Anxiolytics, sedatives and hypnotics

Question 1

What is the single most important inhibitory transmitter in the brain?

Answer 1

GABA

Question 2

What is the single most important excitatory neurotransmitter in the brain?

Answer 2

Glutamate

Question 3

What are the processes involved in GABA neurotransmission?

Answer 3

Action potential arrives down GABAergic axon.

Increase in activity in hippocampus activates GABA neurons, localised control, dampens hippocampal activity.

GABA synthesised from glutamate.

Acted on by glutamate decarboxylase (GAD)- take away one carboxyl group from glutamate to generate GABA in presynaptic nerve terminal.

GABA loaded into vesicles, vesicular pumps suck up GABA and concentrate into presynaptic vesicles.

With arrival of action potential, there is depolarisation of presynaptic terminal and exocytotic release of GABA into cleft.

GABA diffuses across cleft and interacts with postsynaptic receptors- GABA-A receptors: chloride ionophores, ion channel linked (type 1 receptors).

When GABA stimulates GABA-A receptor, protein changes conformation and momentarily open chloride ion channels- chloride influx hyperpolarises postsynaptic cell.

More difficult to excite postsynaptic cell- harder to depolarise to reach threshold membrane potential and thus action potential.

Question 4

How is GABA inactivated?

Answer 4

Reuptake is the first step- into surrounding glial cells or back into presynaptic terminal, reduces synaptic concentration of GABA so it can be metabolised.

First enzyme of GABA metabolism is GABA-T.

Question 5

What are GABA-B receptors?

Answer 5

G-protein coupled type 2 receptors on presynaptic terminals.

Can be stimulated to downregulate release of GABA if high synaptic concentration (negative feedback).

Question 6

What is the first enzyme of GABA metabolism?

Answer 6

GABA transaminase (GABA-T).

Question 7

What are GABA-A receptors?

Answer 7

Chloride ionophores, ion channel linked (type 1 receptors).

When GABA stimulates GABA-A receptor, protein changes conformation and momentarily open chloride ion channels- chloride influx hyperpolarises postsynaptic cell.

More difficult to excite postsynaptic cell- harder to depolarise to reach threshold membrane potential and thus action potential.

Question 8

How is GABA synthesised from glutamate?

Answer 8

Acted on by glutamate decarboxylase (GAD)- take away one carboxyl group from glutamate to generate GABA in presynaptic nerve terminal.

Question 9

What is the precursor to GABA?

Answer 9

Glutamate.

Question 10

How is GABA metabolised?

Answer 10

GABA transaminase (GABA-T) is the first enzyme of GABA metabolism, breaks it down into succinic semialdehyde which is then broken down into succinic acid by succinic semialdehyde dehydrogenase (SSDH). Mitochondrial enzymes.
Succinic acid goes back into TCA cycle.
Glutamate arises from TCA cycle- GABA shunt.

Question 11

What does inhibition of GABA metabolism result in?

Answer 11

Large increase in brain GABA.

Question 12

What is sodium valproate (epilim)?

Answer 12

Anticonvulsant, GABA-T and SSDH inhibitor, sodium channel blocker.

Question 13

What is vigabatrin (sabril)?

Answer 13

Anticonvulsant, GABA-T covalent inhibitor- increase in GABA in presynaptic nerve terminal, dampens hyperactivity in the brain.

Question 14

What are the 4 main protein components of the GABA-A receptor complex?

Answer 14

GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein

Question 15

What happens when GABA activates the GABA-A receptor complex?

Answer 15

When GABA activates receptor, binds to GABA receptor protein and causes linkage of GABA receptor protein with benzodiazepine receptor protein mediated by GABA modulin polypeptide.

Results in momentary opening of chloride channel protein, allowing chloride influx and subsequent hyperpolarisation.

Question 16

What is flumazenil?

Answer 16

Flumazenil is a benzodiazepine antagonist- competitive.

Question 17

How do benzodiazepines interact with the GABA-A receptor complex?

Answer 17

Benzodiazepine binds to BDZ receptor protein and facilitates the action of GABA on the chloride ion channel.

In the presence of a benzodiazepine, binding of GABA is enhanced (increased affinity), reciprocated- in the presence of GABA, binding of benzodiazepine (affinity) is increased.

Question 18

How do barbiturates interact with the GABA-A receptor complex?

Answer 18

Barbiturate binds to barbiturate receptor protein- enhances action of GABA on chloride channel, enhance GABA binding at GABA receptor protein (increased affinity of GABA binding)- not reciprocated; at higher than therapeutic doses can cause direct agonist action on chloride channel.

Question 19

What makes the action of benzodiazepines and barbiturates allosteric?

Answer 19

No activity alone- GABA has to be present, because they work by enhancing it.

Question 20

How are benzodiazepines and barbiturates different?

Answer 20

Different binding sites and different mechanisms.
Benzodiazepines increase frequency of openings.
Barbiturates increase duration of openings.
Barbiturates are less selective than benzodiazepines- decrease excitatory transmission and have other membrane effects, e.g. direct opening effect on chloride channel at higher than therapeutic doses; may explain induction of surgical anaesthesia and low margin of safety.

Question 21

What are the clinical uses of benzodiazepines and barbiturates?

Answer 21

Anaesthetics (barbiturates only: thiopentone, used as inducing agent for general anaesthetic)
Anticonvulsants (diazepam, clonazepam, phenobarbital)
Anti-spastics (diazepam)
Anxiolytics
Sedatives/hypnotics

Question 22

Define anxiolytic.

Answer 22

Remove anxiety without impairing mental or physical activity (‘minor tranquilisers’).

Question 23

Define sedative.

Answer 23

Reduce mental and physical activity without producing loss of consciousness.

Question 24

Define hypnotic.

Answer 24

Induce sleep.

Question 25

What should benzodiazepines and barbiturates ideally do/ not do?

Answer 25

Have wide margin of safety
Not depress respiration
Produce natural sleep (hypnotics)
Not interact with other drugs
Not produce ‘hangovers’
Not produce dependence

Question 26

What are the clinical uses of barbiturates?

Answer 26

Range of clinical uses, including sedative/hypnotic:

• amobarbital
• useful for severe intractable insomnia
• half-life: 20-25 hours

Anaesthetics (thiopentone, used as inducing agent for general anaesthetic).

Anticonvulsants (phenobarbital).

Anxiolytics.

Question 27

What are the unwanted effects of barbiturates?

Answer 27

Not drugs of 1st choice
Low safety margins
Depress respiration
Overdosing lethal
Alter natural sleep (decreased REM) leading to hangovers/irritability
Enzyme inducers
Potentiate effect of other CNS depressants (e.g. alcohol)- increased risk of overdose
Tolerance
Dependence

Question 28

What are the signs/symptoms of withdrawal syndrome due to barbiturate dependence?

Answer 28

Insomnia
Anxiety
Tremor
Convulsions
Death

Question 29

How are benzodiazepines administered?

Answer 29

Well absorbed p.o. (oral)
Peak [plasma] around 1 hour after administration
Can be given intravenously against status epilepticus (tonic clonic)

Question 30

How are benzodiazepines distributed in the body?

Answer 30

Bind plasma proteins strongly

Highly lipid soluble → wide distribution

Question 31

How are benzodiazepines metabolised?

Answer 31

Usually extensively, in the liver.
Long-actings like diazepam are first converted to metabolites or short-actings, then to glucuronide.
Short-actings are converted directly to glucuronide (oxazepam) or via other short-actings (temazepam via oxazepam).

Question 32

How are benzodiazepines excreted?

Answer 32

Urine- glucuronide conjugates.

Question 33

Describe the duration of action of benzodiazepines.

Answer 33

Varies greatly
Short-acting
Long-acting: slow metabolism and/or generate active metabolites

Question 34

What drugs can be used as anxiolytics?

Answer 34

Long-acting benzodiazepines
Diazepam (valium)
Chlordiazepoxide (librium)
Nitrazepam
NB: oxazepam- hepatic impairment, half-life = 8 hours

Question 35

What drugs can be used as sedative hypnotics?

Answer 35

Short-acting benzodiazepines
Temazepam
Oxazepam
NB: nitrazepam- daytime anxiolytic effect, half-life = 28 hours

Question 36

What are the advantages of benzodiazepines?

Answer 36

Wide margin of safety
Overdose → prolonged sleep (rousable)
Flumazenil (competitive antagonist, antidote)
Mild effect on REM sleep
Do not induce liver enzymes

Question 37

What are the unwanted effects of benzodiazepines?

Answer 37

Sedation, confusion, amnesia, ataxia (impaired manual skills)
Potentiate other CNS depressants (alcohol, barbiturates)
Tolerance (less than barbiturates, ‘tissue’ only)
Dependence:
Withdrawal syndrome similar to barbiturates (less intense)
Withdraw slowly
Free [plasma] increased by e.g. aspirin, heparin

Question 38

What is zopiclone?

Answer 38

Short acting sedative/hypnotic (half-life = 5 hours)
Acts at benzodiazepine receptors (cyclopyrrolone)
Similar efficacy to benzodiazepines
Minimal hangover effects but dependency still a problem

Question 39

Other than benzodiazepines, what drugs can be used as anxiolytics?

Answer 39

Some antidepressant drugs:

• SSRIs
• less sedation and dependence/delayed response/long-term treatment

Some antiepileptic drugs, e.g. valproate, tiagabine.

Some antipsychotic drugs, e.g. olanzapine, quetiapine.

Propranolol: improves physical symptoms (reduces tachycardia via beta-1, reduces tremor via beta-2).

Buspirone:

• 5HT1A agonist
• gewer side effects (< sedation)
• slow onset of action (days/weeks)