Anxiolytics and hypnotics

Question 1

What sort of receptors are involved with anxiolytics and hypnotics?

Answer 1

GABA-A receptors

Question 2

What are the four proteins that GABA-A is composed of?

Answer 2

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

Question 3

What does GABA modulin do?

Answer 3

Links together the GABA receptor protein and benzodiazepine receptor protein

Question 4

Where does GABA bind to GABA-A?

Answer 4

The GABA receptor protein

Question 5

What does binding of GABA to GABA receptor protein allow?

Answer 5

It allows GABA modulin to link together the GABA receptor protein and benzodiazepine receptor protein

Question 6

What is the normal physiological action of GABA modulin?

Answer 6

It allows GABA receptor protein and benzodiazepine receptor protein to link and results in opening of chloride channel protein

Question 7

What is bicuculline?

Answer 7

Competitive antagonist for GABA-A receptor

Question 8

Where does benzodiazepine bind to GABA-A?

Answer 8

Benzodiazepine receptor protein

Question 9

What are the two main effects of benzodiazepine binding that facilitates GABA-mediated inhibition?

Answer 9

Facilitates GABA-mediated opening of the chloride channel
Facilitates binding of GABA to its own binding site- increases the affinity of binding of GABA to the GABA binding site.
This effect is then reciprocated

Question 10

What is flumezanil?

Answer 10

Competitive benzodiazepine antagonist

Question 11

Where do barbiturates bind?

Answer 11

They bind to the barbiturate receptor protein

Question 12

What are the 3 effects of barbiturates on GABA neurotransmission?

Answer 12

Facilitates GABA mediated opening of the Cl- channel
Facilitates GABA binding to its receptor but this isn’t reciprocated
At higher concentrations, barbiturates can have direct action on chloride channel

Question 13

How effective are benzodiazepine and barbiturates without GABA?

Answer 13

They have no activity alone

Question 14

How do benzodiazepine and barbiturates have an action?

Answer 14

They enhance the action of GABA, not direct GABA agonists

Question 15

How do benzodiazepines and barbiturates have an allosteric action (at a different site)?

Answer 15

They bind to the GABA-A receptor but bind to their own binding sites on GABA-A

Question 16

How are barbiturates and benzodiazepines different in terms of mechanism?

Answer 16

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

Question 17

Why are barbiturates less safe than benzodiazepines?

Answer 17

Barbiturates are less selective

Question 18

What can barbiturates be used for that benzodiazepines can’t?

Answer 18

Induction of surgical anaesthesia due to reduced selectivity

Question 19

What are the clinical uses of benzodiazepines and barbiturates?

Answer 19

Anaesthetics:
 -Barbiturates only: Thiopentone
Anti-convulsants:
 -Diazepam (bdzp)
 -Clonazepam (bdzp)
 -Phenobarbital (barb)
Anti-spastics
 -Diazepam
Anxiolytics
Sedative

Question 20

How can diazepam be used an an anti-spastic?

Answer 20

It is action in the spinal cord and reduces the propagation of action potentials in alpha motor neurones

Question 21

What is an anxiolytic?

Answer 21

It removes anxiety without impairing mental or physical activity (minor tranquillisers)

Question 22

What is a sedative?

Answer 22

It reduces mental and physical activity without producing loss of consciousness

Question 23

What is a hypnotic?

Answer 23

Induces sleep

Question 24

What should the ideal anxiolytics, sedatives and hypnotics be like?

Answer 24

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

Question 25

What do all barbiturates have in common structurally?

Answer 25

Barbiturate ring- common six membered ring with 4 carbons and 2 nitrogens

Question 26

What is amobarbitral used in?

Answer 26

Severe intractable insomnia

Question 27

Why are barbiturates not first choice drugs for sedative/hypnotic action?

Answer 27

Low safety margin- depress respiration and overdose could be lethal Alter natural sleep (decrease REM sleep)- give rise to hangovers and cause irritability Enzyme inducers (of liver microsomal enzymes- have to be careful when co-adminstering Potentiate the effect of other CNS depressants Tolerance Dependence-associated with withdrawal syndrome: -insomina, anxiety, tremor, convulsions and death

Question 28

What common structure are benzodiazepines?

Answer 28

They are tricyclic compounds that differ in their R1, R2 and R3 groups

Question 29

What are the three key benzodiazepines?

Answer 29

Diazepam Oxazepam Temazepam

Question 30

What is flumezanil?

Answer 30

Competitive benzodiazepine receptor antagonist

Question 31

Why is flumezanil so effective?

Answer 31

It has the same three ring structure as the agonist so it can bind to benzodiazepine receptor but has no efficacy

Question 32

What is the key difference between all benzodiazepines?

Answer 32

Pharmacokinetics (they all have similar potencies and same mechanism)

Question 33

How are benzodiazepines administered?

Answer 33

They are well absorbed per orally They reach peak plasma concentration after about 1 hour Sometimes given IV (treatment of status epileptics)

Question 34

How are benzodiazepines distributed?

Answer 34

They bind to plasma proteins strongly | Highly lipid soluble

Question 35

How are benzodiazepines metabolised?

Answer 35

Extensively in the liver

Question 36

How are benzodiazepines excreted?

Answer 36

In the urine as glucuronide conjugates

Question 37

How much does the duration of action of benzodiazepines change?

Answer 37

It varies a lot, allows classification as short acting or long acting (slower metabolism or generates active metabolites)

Question 38

Name short acting and long acting benzodiazepines?

Answer 38

``` Short acting: Oxazepam Temazepam Long acting: Diazepam ```

Question 39

How is oxazepam metabolised?

Answer 39

In the liver to its inactive glucuronide

Question 40

How is temazepam metabolised?

Answer 40

Initially to oxazepam which is then converted to the glucuronide conjugate

Question 41

How is diazepam metabolised?

Answer 41

IT is metabolised via temazepam and oxazepam to the glucuronide

Question 42

What are benzodiazepines used for?

Answer 42

Anxiolytics (generally longer acting) -Diazepam, chlordiazepoxide and nitrazepam Sedative/hypnotics (generally shorter acting) - Temazepam and oxazepam

Question 43

What are the advantages of benzodiazepines over barbiturates?

Answer 43

Wide margin of safety Prolonged sleep if overdose but it is rousable Flumanezil can be given to reverse overdose Mild effect on REM sleep Doesn't enhance liver enzymes

Question 44

What are the unwanted effects benzodiazepines?

Answer 44

``` Sedation Confusion, ataxia Potentiate other CNS depressants Tolerance Dependence- withdrawal syndrome Free plasma concentration can increase by giving aspirin and heparin ```

Question 45

What is zopiclone?

Answer 45

It is short acting sedative/hypnotic at benzodiazepine receptor but isn't a benzodiazepine. It enhances GABA-mediated neurotransmission by binding to the benzodiazepine binding site but is actually a cyclopyrrolone. It has similar efficacy to benzodiazepines and minimal hangover effects

Question 46

What can propranolol be used for?

Answer 46

It can be used as an anxiolytic because it is a non-selective beta blocker. Improves physical symptoms of anxiety- tachycardia and tremor

Question 47

What is buspirone used for?

Answer 47

It is used an anxiolytic because it is a 5HT1a agonist, has few side effects and there is less sedation compared to benzodiazepines. Downside is slow onset of action