Anxiolytics and Hypnotics

Question 1

What are the four main proteins that make up the GABA-A receptor?

Answer 1

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

Question 2

What protein links the GABA receptor proteins and the benzodiazepine receptor protein?

Answer 2

GABA modulin

Question 3

Name a competitive antagonist of the GABA receptor protein.

Answer 3

Biciculline

Question 4

Name a competitive antagonist of the benzodiazepine receptor protein.

Answer 4

Flumazenil

Question 5

What are the two main effects of benzodiazepines that facilitate GABA neurotransmission?

Answer 5

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

Question 6

What are the three main effects of barbiturates that facilitate GABA neurotransmission?

Answer 6

They enhance the normal physiological action of GABA
They enhance GABA binding to the GABA receptor protein
At higher concentrations, barbiturates can have a direct action on the chloride channel

Question 7

What is the key difference in the mechanism of action of barbiturates and benzodiazepines?

Answer 7

Benzodiazepines – increase the frequency of chloride channel opening
Barbiturates – increase the duration of chloride channel opening

Question 8

What is the relative difference in selectivity between barbiturates and benzodiazepines?

Answer 8

Barbiturates are LESS selective
This may explain why barbiturates induce surgical anaesthesia and why barbiturates are less safe than benzodiazepines
NOTE: barbiturates also reduce excitatory transmission

Question 9

Name a barbiturate that is used as an anaesthetic.

Answer 9

Thiopentone- only barbiturates can be anaesthetics

Question 10

Name three barbiturates and benzodiazepines that are used as anti-convulsants.

Answer 10

Diazepam
Clonazepam
Phenobarbital

Question 11

Name a benzodiazepine that is used as an anti-spastic.

Answer 11

Diazepam

Question 12

What are two other clinical uses of benzodiazepines and barbiturates?

Answer 12

Anxiolytics

Hypnotics

Question 13

Define anxiolytic.

Answer 13

Remove anxiety without impairing mental or physical activity

Question 14

Define sedative.

Answer 14

Reduce mental and physical activity without producing loss of consciousness

Question 15

Define hypnotic.

Answer 15

Induces sleep

Question 16

What structure is common to all barbiturates?

Answer 16

Six-membered ring (4 carbons and 2 nitrogens)

Question 17

Barbiturates have been largely superseded by benzodiazepines. Which barbiturate is still used relatively commonly?

Answer 17

Amobarbital- for insomnia

Question 18

What are the unwanted effects of barbiturates?

Answer 18

Low safety margin (overdose can be lethal)
Alters natural sleep (reduced REM)
Enzyme inducers
Potentiate the action of other CNS depressants (e.g. alcohol)
Tolerance
Dependence

Question 19

What structure is common to all benzodiazepines?

Answer 19

They are tricyclic

Question 20

What are the three key benzodiazepines?

Answer 20

Diazepam
Oxazepam
Temazepam

Question 21

What is the difference between all the benzodiazepines that are in clinical use?

Answer 21

Their pharmacokinetics

Question 22

Describe the administration of benzodiazepines.

Answer 22

Well absorbed per orally

Peak plasma concentration after about 1 hour

Question 23

When would you give IV benzodiazepines?

Answer 23

Treatment of status epilepticus

Question 24

Describe the distribution of benzodiazepines.

Answer 24

Bind strongly to plasma proteins

Highly lipid soluble

Question 25

Describe the metabolism of benzodiazepines.

Answer 25

Extensively metabolised in the liver

Question 26

Describe the excretion of benzodiazepines.

Answer 26

Excreted in the urine as glucuronide conjugates

Question 27

Describe the duration of action of benzodiazepines.

Answer 27

Varies a lot | This allows classification as short-acting and long-acting benzodiazepines

Question 28

What makes long-acting benzodiazepines have a long duration of action?

Answer 28

They have slower metabolism | They generate active metabolites

Question 29

Name two short-acting benzodiazepines.

Answer 29

Oxazepam | Temazepam

Question 30

Name a long-acting benzodiazepine.

Answer 30

Diazepam

Question 31

Describe the metabolism of oxazepam.

Answer 31

It is metabolised straight to its glucuronide conjugate (t1/2 = 8 hours)

Question 32

Describe the metabolism of temazepam.

Answer 32

Metabolised to oxazepam and then to the glucuronide conjugate

Question 33

Describe the metabolism of diazepam.

Answer 33

Metabolised via temazepam and oxazepam to the glucuronide conjugate Some diazepam is metabolised to nordiazepam and then oxazepam

Question 34

Name three drugs that are used as anxiolytics.

Answer 34

General rule – long-acting benzodiazepines Diazepam Chlordiazepoxide Nitrazepam

Question 35

Under what condition would you use a short-acting benzodiazepine as an anxiolytic?

Answer 35

Hepatic impairment – this means that the benzodiazepines and metabolised more slowly – drug of choice = oxazepam

Question 36

Name two drugs that are used as sedatives/hypnotics.

Answer 36

General rule – short-acting benzodiazepines Oxazepam Temazepam

Question 37

Name a long acting drug that might be used as a sedative/hypnotic.

Answer 37

Nitrazepam (t1/2 = 28 hours)

Question 38

What are the advantages of benzodiazepines over barbiturates?

Answer 38

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

Question 39

What are the unwanted effects of benzodiazepines?

Answer 39

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

Question 40

Name a sedative/hypnotic that isn’t a benzodiazepine. What class of drug does this fall into?

Answer 40

Zopiclone – this is a cyclopyrrolone and it’s short-acting (t1/2 = 5 hours) NOTE: it acts on the benzodiazepine receptor but it is not a benzodiazepine This has fewer hangover effects but dependency is still an issue

Question 41

What drug is used to control the physical symptoms of anxiety?

Answer 41

Propranolol

Question 42

Name a new drug that has started being used as an anxiolytic.

Answer 42

Buspirone – 5HT1A agonist

Question 43

Synthesis of GABA

Answer 43

Glutamine to GABA via glutamate decarboxylase

Question 44

Where is GABA reuptaken to

Answer 44

Presynaptic membrane | Glial cell

Question 45

What are most GABAergic neurones

Answer 45

short interneurones in specific brain areas

Question 46

Metabolism of GABA first step

Answer 46

GABA to succinic semialdehyde via GABA transaminase

Question 47

Metabolism of GABA second step

Answer 47

Succininc semialdehyde to succinic acid using succinic semialdehyde dehydrogenase

Question 48

What are features of GABA metabolism enzymes

Answer 48

Mitochondrial enzymes

Question 49

Things to consider when designing barb and BZ drug

Answer 49

``` Wide margin of safety Not depress respiration Produce natural sleep for hypnotics Not interact with other drugs Not produce hangovers Not produce a dependence ```