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

Describe the normal physiological action of GABA.

Answer 3

GABA binds to the GABA receptor protein
GABA modulin links the GABA receptor protein and the benzodiazepine receptor protein
This results in opening of the chloride ion channel

Question 4

Name a competitive antagonist of the GABA receptor protein.

Answer 4

Biciculline

Question 5

Name a competitive antagonist of the benzodiazepine receptor protein.

Answer 5

Flumazenil

Question 6

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

Answer 6

They facilitate the GABA-mediated opening of the chloride channel
They facilitate the binding of GABA to its receptor protein (increase theaffinity of GABA to the GABA binding site) – this is reciprocated

Question 7

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

Answer 7

They enhance the normal physiological action of GABA
They enhance GABA binding to the GABA receptor protein (NOT reciprocated)
At higher concentrations, barbiturates can have a direct action on the chloride channel

Question 8

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

Answer 8

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

Question 9

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

Answer 9

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 10

Name a barbiturate that is used as an anaesthetic.

Answer 10

Thiopentone

Question 11

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

Answer 11

Diazepam
Clonazepam
Phenobarbital

Question 12

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

Answer 12

Diazepam

Question 13

What are two other clinical uses of benzodiazepines and barbiturates?

Answer 13

Anxiolytics

Hypnotics

Question 14

Define anxiolytic.

Answer 14

Remove anxiety without impairing mental or physical activity

Question 15

Define sedative.

Answer 15

Reduce mental and physical activity without producing loss of consciousness

Question 16

Define hypnotic.

Answer 16

Induces sleep

Question 17

What structure is common to all barbiturates?

Answer 17

Six-membered ring (4 carbons and 2 nitrogens)

Question 18

Barbiturates have been largely superseded by benzodiazepines.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

Answer 18

Amobarbital

Question 19

What is the half-life of this drug?

Answer 19

20-25 hours

Question 20

What are the unwanted effects of barbiturates?

Answer 20

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 21

What structure is common to all benzodiazepines?

Answer 21

They are tricyclic

Question 22

What are the three key benzodiazepines?

Answer 22

Diazepam
Oxazepam
Temazepam

Question 23

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

Answer 23

Their pharmacokinetics

Question 24

Describe the administration of benzodiazepines.

Answer 24

Well absorbed per orally

Peak plasma concentration after about 1 hour

Question 25

When would you give IV benzodiazepines?

Answer 25

Treatment of status epilepticus

Question 26

Describe the distribution of benzodiazepines.

Answer 26

Bind strongly to plasma proteins | Highly lipid soluble

Question 27

Describe the metabolism of benzodiazepines.

Answer 27

Extensively metabolised in the liver

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

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

Question 30

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

Answer 30

They have slower metabolism | They generate active metabolites

Question 31

Name two short-acting benzodiazepines.

Answer 31

Oxazepam | Temazepam

Question 32

Name a long-acting benzodiazepine.

Answer 32

Diazepam

Question 33

Describe the metabolism of oxazepam.

Answer 33

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

Question 34

Describe the metabolism of temazepam.

Answer 34

Metabolised to oxazepam and then to the glucuronide conjugate

Question 35

Describe the metabolism of diazepam.

Answer 35

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

Question 36

Name three drugs that are used as anxiolytics.

Answer 36

General rule – long-acting benzodiazepines Diazepam Chlordiazepoxide Nitrazepam

Question 37

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

Answer 37

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

Question 38

Name two drugs that are used as sedatives/hypnotics.

Answer 38

General rule – short-acting benzodiazepines Oxazepam Temazepam

Question 39

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

Answer 39

Nitrazepam (t1/2 = 28 hours)

Question 40

What are the advantages of benzodiazepines over barbiturates?

Answer 40

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 41

What are the unwanted effects of benzodiazepines?

Answer 41

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 42

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

Answer 42

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 43

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

Answer 43

Propranolol

Question 44

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

Answer 44

Buspirone – 5HT1A agonist This has relatively few side effects and causes less sedation than benzodiazepines Downside: slow onset of action (maximal anxiolytic effects are not seen for a number of days/weeks)