Anxiolytics and Hypnotics

Question 1

What is the difference between anxiolytics and hypnotics?

Answer 1

anxiolytics are a class of drugs used to treat anxiety disorders

hypnotics are a class of drugs used to treat insomnia

Question 2

What is insomnia? What are the different classes?

Answer 2

insomnia is a sleep disorder in which there are regular problems with sleeping
- e.g. find it hard to fall asleep, lie awake during the night

insomnia can be triggered by anxiety

can be

• transient = momentary e.g. jet lag
• short term = persists of several weeks or until the stress subsides
• chronic = last for 3 or more weeks e.g. drug and alcohol abuse

Question 3

What is the difference between low, high and toxic doses of anxiolytics and hypnotics?

Answer 3

low dose
- anxiolytics

high dose

• sedation and sleep
• anaesthesia

toxic dose

• coma
• respiratory depression

Question 4

What are the different types of treatments?

Answer 4

benzodiazepines and z-drugs (not used)
barbiturates (not used)
5-HT1a receptor agonist
beta noradrenergic receptor antagonist

Question 5

What is GABA? What is the difference between GABAa and GABAb?

Answer 5

GABA

• inhibitory neurotransmitter
• activates ligand gated ion channels or G-protein coupled receptors
• are found in local circuit interneurons

GABAa
- ligand gated ion channel = chloride ions
GABAb
- G-protein couple receptor

Question 6

What is the structure of GABAa?

Answer 6

ligand gated chloride channel

pentameric structure
- have five subunits
= most common configuration is 2 alpha, 2 beta and 1 gamma

have pockets where drugs can bind

• benzodiazepine binding site = alpha gamme interface
• channel blockers = picrotoxin
• channel modulators = general anaesthetics
• agonists/antagonists
• allosteric modulators = barbiturates

Question 7

What are barbiturates? How do barbiturates act? What is their effect?

Answer 7

are a class of GABAa receptor positive allosteric modulators (PAMs)

increases the activity of GABAa receptors
- binding increases channel opening

is a direct GABA agonist (increased inhibition)
stabilises glycine open channel (increased inhibition)

blocks nicotinic acetylcholine receptor and serotonin receptors (reduced excitation)
blocks AMPA and kainate receptors (reduced excitation via glutamate receptor blockage)

Question 8

What are barbiturates used to treat? Why are they no longer used as anxiolytics/hynotics?

Answer 8

have a severe CNS depressant effect
- GABA agonist, opens glycine channels, blocks nAchR and glutamate receptors (AMPA/kainate)

are used in epilepsy and general anaesthesia

Question 9

What are benzodiazepines? How do benzodiazepines act? What is their effect?

Answer 9

are a class of GABAa receptor positive allosteric modulators (PAMs)
- bind to a distinct regulatory site on GABAa receptors (alpha-gamma interface)

stabilise the GABAa receptor binding site for GABA in the open configuration
- increases GABA affinity for its binding site and enhances its neuroinhibitory actions

bind at a site different to GABA acting only when GABA is present

Question 10

Why are benzodiazepines preferred over barbiturates?

Answer 10

benzodiazepines are “cleaner” than barbiturates
- they do not activate other receptors (e.g. glycine, glutamate receptors)
= do not have a severe CNS depressant effect

Question 11

What is flumazenil? Why is it useful?

Answer 11

is able to reverse the sedative effects of benzodiazepines

- is a competitive antagonist at the benzodiazepine binding site (alpha-gamma interface)

Question 12

What are examples of benzodiazepines? What is their duration of action? What can they function as?

Answer 12

midazolam
- less than 6 hour = shortest duration
= anaesthetic

temazepam
- 12-18 hours
= hypnotic

diazepam
- 24-28 hours
= anxiolytic, anti-convulsant, treatment for alcohol withdrawal

chlordiazepoxide
- 24-28 hours = longest duration
= anxiolytic, treatment for alcohol withdrawal

Question 13

How can benzodiazepines and barbiturates lead to tolerance, dependence and addiction?

Answer 13

symptomatic
- in anxiety, GABA levels are often low (GABA and glutamate imbalance)

benzodiazepines
- act as positive allosteric modulators at the GABAA receptor to stabilise the GABAA receptor binding site for GABA in the open configuration
= increases GABA affinity for its binding site

tolerance
- develop tolerance (a gradual escalation of dose needed to produce the required effect)
= due to the trafficking of additional glutamate receptors to the cell membrane

withdrawal
- there is a sudden decrease in inhibitory GABA neurotransmission coupled with increased excitatory glutamate neurotransmission
= can lead to heightened anxiety and various other side-effects (e.g. tremor, dizziness and even convulsions).

Question 14

How can benzodiazepines and barbiturates be used to treat alcohol dependence?
- moderate to severe

Answer 14

healthy individual
- balance in neurotransmission of GABA and glutamate

excessive alcohol consumption
- imbalance between GABA and glutamate
= GABA neurotransmitter levels are increased
- leads to the trafficking of additional glutamate receptors to the cell membrane

withdrawal
- sudden decrease in inhibitory GABA neurotransmission coupled with increased excitatory glutamate neurotransmission
= can lead to the development of side-effects including potential convulsions

individuals should be titrated off benzodiazepines

Question 15

What are Z-drugs? How do they work?

Answer 15

Z-drugs (e.g. zolpidem, zopiclone) are a class of GABAa receptor positive allosteric modulators that are used as hypnotics

bind to the benzodiazepine binding site (alpha-gamma interface) on the GABAa receptor
- but are structurally different
= lack the charateristic benzene ring and diazepam ring fusion

are ultrashort/short-acting
- are suitable for use as hypnotics but NOT as anxiolytics

Question 16

What are 5-HT 1A receptors agonists? How do they work?

Answer 16

activates 5-HT1A auto-receptors

e.g. buspirone
- are a class of drugs primarily used to treat generalised anxiety disorder (GAD)
= activates 5-HT1A auto-receptors and inhibits the activation of NA neurons

has fewer side effects than benzodiazepines
- less sedative and addictive but can cause dizziness, nausea and headache

takes several days to take effect

Question 17

What is the function of 5-HT agonists?

Answer 17

activates GPCR sub-types (5-HT1 - 5-HT7) and 5-HT3 ligand-gated ion channel

roles in sleep and wakefulness, mood and emotional behaviours
- regulates the sleep wake cycle by linking rhythmic activity in the basal fore brain and preoptic area to the circadian rhythm

is a key drug target for depression (e.g. SSRI’s) and anxiety disorders (e.g. 5-HT1A agonists)

Question 18

What is the mechanism of action of buspirone?

Answer 18

initially inhibits 5-HT release 
it can induce desensitisation of auto-inhibitory 5-HT1A receptors the longer its taken
downregulation of 5-HT1A receptors 
more excitation of serotonergic neurons
more 5-HT release

inhibits the activation of NA neurons
- decreases arousal

Question 19

What is noradrenaline? What are beta adrenergic receptor antagonists? What is their mechanism of action?

Answer 19

noradrenaline activate GPCR subtypes

• alpha and beta-noradrenergic receptor
• has roles in the CNS in attention, arousal and sleep and wakefulness

beta noradrenergic antagonists reduce some of the peripheral manifestations of anxiety
- tachycardia, sweating, GI problems and tremor

propranolol
- works by blocking peripheral sympathetic responses (“fight or flight”) rather than central effects